Publications-Theses
Article View/Open
Publication Export
-
Google ScholarTM
NCCU Library
Citation Infomation
Related Publications in TAIR
題名 IFITM基因剔除鼠之下視丘功能之缺失研究
Study of hypothalamus dysfunctions in IfitmDel mutant mice作者 林万焜
Lin, Wan-Kun貢獻者 陳紹寬
Chen, Shau-Kawun
林万焜
Lin, Wan-Kun關鍵詞 IFITM基因剔除鼠
下視丘發炎
下視丘功能破壞
IfitmDel mice
Hypothalamic inflammation
Hypothalamic dysfunctions日期 2017 上傳時間 2-Feb-2018 11:24:43 (UTC+8) 摘要 Ifitm基因是一群可被干擾素刺激表現的基因，目前已知這些基因參與細胞對病毒的防禦，然而其生化特性及這些基因參與的其他生物功能並不清楚。將這些基因敲除後小鼠會產生過度攝食的行為並會造成肥胖，同時在下視丘中黑皮質素的前驅物POMC的表現量顯著降低，此發現表明破壞Ifitm基因可導致下視丘功能被破壞。然而由於代謝的調控並非只由下視丘控制，Ifitm基因是否直接參與下視丘的功能並不清楚。本研究卽是在探討Ifitm基因是否在下視丘的功能中扮演重要的角色。我們首先透過與下視丘功能有關的行為分析測試是否有其他下視丘功能被破壞的證據。我們發現在IFITM基因剔除公鼠，3-6個月開始出現過度攝食的行為與體重明顯增加；然而IFITM基因剔除母鼠在18個月後才出現同樣的表現型。IFITM基因剔除公鼠，在OFT與FST的行為測試中行動力下降，IFITM基因剔除母鼠卻有較多的活動；在公鼠與母鼠中焦慮均顯著增加。我們進一步測試這些剔除鼠的下視丘組織及神經胜肽的表現，在組織分析中並沒有發現組織結構異常。在神經胜肽的分析中IFITM基因剔除鼠的CRF的表現量增加，與IFITM基因剔除鼠的焦慮行為顯示相同趨勢。POMC表現的減少與CRF表現的上升顯示下視丘的功能紊亂。我們同時發現IFITM基因剔除鼠中微膠細胞數增加，以及位於下視丘的細胞本體的體積增加。另外IFITM基因剔除鼠中的細胞激素TNF-α與IL-1β在周邊血清中的增加表明此剔除鼠的下視丘產生發炎。本研究發現剔除IFITM基因會造成多項下視丘功能受到影響，並發現此突變鼠有下視丘發炎的現象。此下視丘發炎是否為下視丘功能破壞的主因，及IFITM基因剔除鼠的下視丘功能異常的細胞分子機制將會進一步被分析。
Ifitm genes are a group of interferon-inducible genes, best known for their antiviral roles. Their biological functions other than cellular antivirus and the biochemical properties of these proteins are not well-understand. Previously age-dependent hyperphagia and obesity were reported in IfitmDel mutant mice, in which 5 Ifitm genes were deleted. The levels of pro-opiomelanocortin (POMC) in hypothalamus of these mice were significantly reduced, suggesting that the hyperphagia phenotype of IfitmDel mutants is caused by defective central melanocortin signaling. In this study, we examine whether the hypothalamic dysfunctions are developed in these mutants. Whether hypothalamus associated behaviors are disrupted in IfitmDel mutants was first examined. We discovered that the hyperphagia and obesity phenotype in IfitmDel mutants are gender-dependent. These phenotypes in male mutants are detectable starting from 4-6 months of age, but not detected until one-year old in female mutants. Male mutants reveal the trends of decreased activities, while female mutants exhibit increased locomotor activity. Both gender develop anxiety-like phenotype. The behavioral abnormalities support the hypothesis of hypothalamic dysfunctions. As the Ifitm genes are expressed in various stage during development, the anatomy and the functions of the hypothalamus of these mutants were further tested. The histological analyses show no anatomical defects, neuron count differences and morphological alterations of neurons in IfitmDel mutant brains of both genders. These results indicate that these proteins are rather crucial for maintaining normal physiology in the developed central nervous system (CNS). The expression levels of neuropeptides related to stress response and anxiety or depression status, such as corticotrophin releasing factor (CRF), are altered in mutant hypothalamus. In contrast, Cell count and cell body size of microglia, whereas sera levels of pro-inflammatory cytokines, including TNF-α and IL-1β are elevated in IfitmDel mice, indicating hypothalamic inflammation and microglial activation phenotypes. The cellular mechanisms underlying the hypothalamic dysfunctions and the causative relationship of the hypothalamic inflammation with these phenotypes shall be further explored in the future studies.參考文獻 Anand BK et al. (1951) Hypothalamic control of food intake in rats and cats. The Yale journal of biology and medicine 24:123.Anderberg RH et al. (2016) GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality. Psychoneuroendocrinology 65:54-66.Anisman H et al. (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci16(3–4):149–64.Aponte Y, Atasoy, D. & Sternson, S. M. (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci 14, 351–355.Arborelius L OM, Plotsky PM, Nemeroff CB. (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160(1):1–12.Bailey CC et al. (2014) IFITM-Family Proteins: The Cell`s First Line of Antiviral Defense. Annu Rev Virol 1:261-283.Bailey CC KH, Huang IC, Farzan M (2013) Interferon-induced transmembrane protein 3 is a type II transmembrane protein. J Biol Chem 288:32184-93.Bale TL VW (2004 ) CRF AND CRF R ECEPTORS:Role in Stress Responsivity and Other Behaviors. Annu Rev Pharmacol Toxicol Feb 10;44(1):525–57. .Barsh GS, Farooqi, I.S. & O`Rahilly, S. (2000) Genetics of body-weight regulation. . Nature 404, 644–651.Beaumont D et al. (1983) Synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines and their actions at adrenoceptors in vivo and in vitro. J Med Chem 26:507-515.Brass AL et al. (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139:1243-1254.Bray GA et al. (1979) Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiological Reviews 59:719-809.Butler AA (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. . Endocrinology 141, 3518–3521.Cai D YM, Frantz DF, Melendez PA, Hansen L, et al. ( 2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-βand NF-κB. . Nat Med 11:183–90.Chen YX et al. (1984) Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen. J Immunol 133:2496-2501.Chuang JC et al. (2010) Ghrelin`s Roles in Stress, Mood, and Anxiety Regulation. Int J Pept 2010.Coleman DL (1973) Effects of parabiosis of obese with diabetes and normal mice. . Diabetologia 9, 294–298 (1973) Coleman DLH, K.P. (1969) Effects of parabiosis of normal with genetically diabetic mice. Am. J. . Physiol 217, 1298–1304 (1969) Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci pp. 571-578.D. Atasoy JNB, H.H. Su, S.M. Sternson (2012) Deconstruction of a neural circuit for hunger. Nature 488 (2012), pp. 172-177.Dallman MF et al. (2007) Glucocorticoids and insulin both modulate caloric intake through actions on the brain. J Physiol 583:431-436.Dandona P et al. (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4-7.Danguir J et al. (1980) Intravenous infusions of nutrients and sleep in the rat: an ischymetric sleep regulation hypothesis. American Journal of Physiology-Endocrinology And Metabolism 238:E307-E312.Deblandre GA et al. (1995) Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth. J Biol Chem 270:23860-23866.Deussing J CA, Dedic N ( 2017) The CRF family of neuropeptides and their receptors—mediators of the central stress response. Curr Mol Pharmacol Mar 2;10(999):1–1. .Diamond MS et al. (2013) The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13:46-57.Dimond S (1978) Depletion of awareness and double-simultaneous stimulation in split-brain man. Cortex 14:604-607.Donath MY B-SM, Ellingsgaard H, Halban PA, Ehses JA. (2010) Cytokine production by islets in health and diabetes: cellular origin, regulation and function. . Trends EndocrinolMetab 21:261-67.E.M. Parise NL, K. Kay, A.M. Dossat, R. Seth, J.M. Overton, D.L. Williams (2011) Evidence for the role of hindbrain orexin-1 receptors in the control of meal size. Am J Physiol Regul Integr Comp Physiol R1692-R1699.Ehses JA B-SM, Faulenbach M, Donath MY. (2008) Macrophages, cytokines and β-cell death in Type 2 diabetes. . Biochem Soc Trans 36:340–42.Epstein H (1971) The origin of the domestic animals of Africa: Africana Publishing Corporation.Evans SS et al. (1990) Monoclonal antibody to the interferon-inducible protein Leu-13 triggers aggregation and inhibits proliferation of leukemic B cells. Blood 76:2583-2593.Everitt AR et al. (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484:519-523.Farooqi IS (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348, 1085–1095 (2003).Fonberg E (1969) The role of the hypothalamus and amygdala in food intake, alimentary motivation and emotional reactions. Acta Biol Exp 29:335-358.Fonberg E (1972) Control of emotional behaviour through the hypothalamus and amygdaloid complex. Physiology, emotion and psychosomatic illness:131-161.Frey M et al. (1997) Tyrosine kinase-dependent regulation of L-selectin expression through the Leu-13 signal transduction molecule: evidence for a protein kinase C-independent mechanism of L-selectin shedding. J Immunol 158:5424-5434.Friedman RL et al. (1984) Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38:745-755.G. A (1994) Regulation of pituitary ACTH secretion during chronic stress. Front Neuroendocrinol. 1994; 15(4):321–50.G.A. Bewick JVG, W.S. Dhillo, A.S. Kent, N.E. White, Z. Webster, M.A. Ghatei, S.R. Bloom (2005) Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J, 19, pp 1680-1682.Gold PW et al. (1986) Abnormal hypothalamic–pituitary–adrenal function in anorexia nervosa. New England Journal of Medicine 314:1335-1342.GS. H ( 2006) Inflammation and metabolic disorders. Nature 444:860–67.Hanagata N et al. (2011) Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. Journal of bone and mineral metabolism 29:279-290.Harrold JA et al. (2012) CNS regulation of appetite. Neuropharmacology 63:3-17.Herman JP MJ, Ghosal S, Kopp B, Wulsin A, Makinson R (2016) Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. In: Comprehensive Physiology Hoboken, NJ, USA: John Wiley & Sons, Inc p. 603–21.Isaacson P (1982) Immunoperoxidase study of the secretory immunoglobulin system in colonic neoplasia. J Clin Pathol 35:14-25.J.E. Blevins MWS, D.G. Baskin (2004) Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol pp. R87-R96.J.N. Betley SX, Z.F. Cao, R. Gong, C.J. Magnus, Y. Yu, S.M. Sternson (2015) Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature, 521, pp 180-185.Jia R et al. (2012) The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization. J Virol 86:13697-13707.Joëls M BTTn-sos (2009) The neuro-symphony of stress. Nat Rev Neurosci 2;10(6):459–66.Jun Chen ANE, Ying Liu (2012) Maternal deprivation in rats is associated with corticotropin releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol July ; 24(7): 1055–1064 doi:101111/j1365-2826201202306x.K. Rahmouni DAM (2007) Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension, 49, pp 647-652.Kalatzis V et al. (2004) Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Hum Mol Genet 13:1361-1371.Kandel ER et al. (2000) Principles of neural science: McGraw-hill New York.Kevin W Williams JKE (2012) From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nature Neuroscience15,1350–1355(2012)doi:101038/nn3217.Koch M et al. (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50.Koch M, Varela, L., Kim, J.G., Kim, J.D., Herna (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519,45–50.Koch M VL, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM6, Rakic P, Bechmann I, Cowley MA4, Szigeti-Buck K, Dietrich MO9, Gao XB, Diano S, Horvath TL (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 2015 Mar 5;519(7541):45-50 doi: 101038/nature14260 2015 Mar 5;519(7541):45-50. doi: 10.1038/nature14260.Krashes MJ (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121, 1424–1428 L. J (2005) Hypothalamic-pituitary-adrenocortical axis regulation. . Endocrinol Metab Clin North Am 2005; 34(2):271–92 vii.L.Horvath MJWT (2015) Neuronal Regulation of Energy Homeostasis: Beyond the Hypothalamus and Feeding. Cell Metabolism Volume 22, Issue 6.Lange UC et al. (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1.Lange UC et al. (2008) Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster. Mol Cell Biol 28:4688-4696.Lewin AR et al. (1991) Molecular analysis of a human interferon-inducible gene family. Eur J Biochem 199:417-423.Lindemann M (1973) The limbic system, its relationship to autonomic regulations and emotions. Zeitschrift fur arztliche Fortbildung 67:322.Lutter M et al. (2009) Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr 139:629-632.M.A. Cowley RGS, S. Diano, M. Tschöp, N. Pronchuk, K.L. Grove, C.J. Strasburger, M. Bidlingmaier, M. Esterman, M.L. Heiman, et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron, 37, pp 649-661.Marc Schneeberger RG, Marc Claret (2013) Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J Endocrinol February 220 T25-T46 Mason BL et al. (2014) The central nervous system sites mediating the orexigenic actions of ghrelin. Annu Rev Physiol 76:519-533.Meyerson BJ (1979) Hypothalamic hormones and behaviour. Med Biol 57:69-83.Mifflin SW et al. (2007) Obesity and the central nervous system. J Physiol 583:423.Miyake Y et al. (2010) Brain activation during the perception of distorted body images in eating disorders. Psychiatry Res 181:183-192.Moffatt P et al. (2008) Bril: a novel bone‐specific modulator of mineralization. Journal of Bone and Mineral Research 23:1497-1508.Ozsoy S et al. (2016) The Effects of Antidepressants on Neuropeptide Y in Patients with Depression and Anxiety. Pharmacopsychiatry 49:26-31.P. Holzer FR, A. Farzi (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 46 (6), pp. 261-274.Plotsky PM MME (1993) postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. . BrainRes Mol Brain Res 1993; 18(3):195–200.Razzoli M et al. (2017) Stress, overeating, and obesity: Insights from human studies and preclinical models. Neuroscience & Biobehavioral Reviews.Regev L BT (2014 ) Corticotropin releasing factor in neuroplasticity. Front Neuroendocrinol. Front Neuroendocrinol Apr;35(2):171–9.Reid LE et al. (1989) A single DNA response element can confer inducibility by both alpha-and gamma-interferons. Proceedings of the National Academy of Sciences 86:840-844.Rossi J (2011) Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. . Cell Metab 13, 195–204 (2011).S.M. Harlan DAM, K. Agassandian, D.F. Guo, M.D. Cassell, C.D. Sigmund, A.L. Mark, K. Rahmouni (2011) Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res, 108, pp 808-812.Saper CB et al. (2014) The hypothalamus. Current Biology 24:R1111-R1116.Saper CB et al. (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36:199-211.Schoggins JW et al. (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481-485.Schulkin J (1991) The allure of salt. Psychobiology 19:116-121.Stellar E (1954) The physiology of motivation. Psychological review 61:5.Stellar E et al. (1991) Neuroendocrine factors in salt appetite. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 42:345-355.Sutton GM (2006) Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors. Endocrinology 147, 2183–2196.Swenson RS (2006) Review of clinical and functional neuroscience. Educational Review Manual in Neurology.Takahashi S et al. (1990) TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen. The Journal of Immunology 145:2207-2213.Tanaka SS et al. (2002) Developmentally regulated expression of mil-1 and mil-2, mouse interferon-induced transmembrane protein like genes, during formation and differentiation of primordial germ cells. Mech Dev 119 Suppl 1:S261-267.Teitelbaum P et al. (1962) The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychological review 69:74.Vale W et al. (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394-1397.Vale W et al. (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245-270.Vale W RC, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J. (1983) Chemical and biological characterization of corticotropin releasing factor. . Recent Prog Horm Res1983:39245–70.Vale W SJ, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 18;213(4514):1394–7.Wee YS et al. (2012) Interferon-inducible transmembrane proteins of the innate immune response act as membrane organizers by influencing clathrin and v-ATPase localization and function. Innate immunity 18:834-845.Weisberg SP MD, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. (2003) Obesity isassociated with macrophage accumulation in adipose tissue. . J Clin Investig 112:1796–808.Williams KW (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. . J Neurosci 30, 2472–2479.Williams KW, Scott, M.M. & Elmquist, J.K. (2011) Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network. Eur J Pharmacol 660, 2–12 (2011) Woods SC et al. (1998) Signals that regulate food intake and energy homeostasis. Science 280:1378-1383.Woods SC, Seeley, R.J., Porte, D. Jr. & Schwartz, M.W. S (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378-1383 (1998) Xu H BG, Yang Q, Tan G, Yang D, et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 112:1821–30.Y. Kuperman MW, J. Dine, K. Staikin, O. Golani, A. Ramot, T. Nahum, C. Kuhne, Y. Shemesh, W. Wurst, A. Harmelin, J.M. Deussing, M. Eder, A. Chen (2016) CRFR1 in AgRP neurons modulates sympathetic nervous system activity to adapt to cold stress and fasting. Cell Metab, 23, pp 1185-1199.Y.C. Shi JL, Z. Lin, H. Zhang, L. Zhai, G. Sperk, R. Heilbronn, M. Mietzsch, S. Weger, X.F. Huang, R.F. Enriquez, P.A. Baldock, L. Zhang, A. Sainsbury, H. Herzog, S. Lin (2013) Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab, 17, pp 236-248.Yeo GSH, L.K. (2012) Unraveling the brain regulation of appetite: lessons from genetics. Nat. Neurosci. 15, xxx–yyy (2012). .Yin Shen Wee JJW, Lorise C. Gahring, Scott W. Rogers, John H. Weis (2015) Age-Related Onset of Obesity Corresponds with Metabolic Dysregulation and Altered Microglia Morphology in Mice Deficient for Ifitm Proteins. In. PLoS ONE 10(4): e0123218. doi:10.1371/journal.pone.0123218.Yount JS et al. (2012) S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus. J Biol Chem 287:19631-19641.Zhang Y (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.Zhang Z et al. (2012) Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One 7:e49265.Zigman JM et al. (2003) Minireview: From anorexia to obesity--the yin and yang of body weight control. Endocrinology 144:3749-3756.Moy S, Nadler J, Perez A, Barbaro R, Johns J, Magnuson T, Piven J, Crawley J (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic‐like behavior in mice. Genes, Brain and Behavior 3:287-302.Sunyer B, Patil S, Höger H, Lubec G (2016) Barnes maze, a useful task to assess spatial reference memory in the mice. Protoc Exchange 2007. In.Ahima RS, Antwi DA (2008) Brain regulation of appetite and satiety. Endocrinology and metabolism clinics of North America 37:811-823.Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491-495.Czaja JA, Goy RW (1975) Ovarian hormones and food intake in female guinea pigs and rhesus monkeys. Hormones and Behavior 6:329-349.Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4-7.Dietrichs E (1984) Cerebellar autonomic function: direct hypothalamocerebellar pathway. Science 223:591-593.DL C (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 9 9, 294–298 (1973).Eckel LA, Houpt TA, Geary N (2000) Spontaneous meal patterns in female rats with and without access to running wheels. Physiology & behavior 70:397-405.Emanuela F, Grazia M, Marco DR, Maria Paola L, Giorgio F, Marco B (2012) Inflammation as a link between obesity and metabolic syndrome. Journal of nutrition and metabolism 2012.Everitt AR, et al. (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484:519-523.Fang P-H, Yu M, Ma Y-P, Li J, Sui Y-M, Shi M-Y (2011) Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior. Neuroscience bulletin 27:407-412.Ford ES (2005) Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome. Diabetes care 28:1769-1778.Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N (2002) Removal of visceral fat prevents insulin resistance and glucose intolerance of aging. Diabetes 51:2951-2958.Garcia-Caceres C, et al. (2016) Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability. Cell 166:867-880.Gong EJ, Garrel D, Calloway DH (1989) Menstrual cycle and voluntary food intake. The American journal of clinical nutrition 49:252-258.Graybiel AM, Rauch SL (2000) Toward a neurobiology of obsessive-compulsive disorder. Neuron 28:343-347.Hetherington A, Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. American Journal of Physiology--Legacy Content 136:609-617.Hetherington A.W. and Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol 136, 609–617.Hong J, Stubbins RE, Smith RR, Harvey AE, Núñez NP (2009) Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutrition journal 8:11.Jacobson L (2005) Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 34:271-292, vii.Jana M, Dasgupta S, Ghorpade A, Pahan K (2008) Astrocytes, oligodendrocytes, and Schwann cells. In: Neuroimmune Pharmacology, pp 69-88: Springer.Johnson RT, Breedlove SM, Jordan CL (2010) Astrocytes in the amygdala. Vitam Horm 82:23-45.Lange UC, Saitou M, Western PS, Barton SC, Surani MA (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1.Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632-635.Liang J, Matheson B, Kaye W, Boutelle K (2014) Neurocognitive correlates of obesity and obesity-related behaviors in children and adolescents. International journal of obesity (2005) 38:494.Lladó I, Rodríguez‐Cuenca S, Pujol E, Monjo M, Estrany ME, Roca P, Palou A (2002) Gender effects on adrenergic receptor expression and lipolysis in white adipose tissue of rats. Obesity 10:296-305.Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-2117.Mahoney CP, Weinberger E, Bryant C, Ito M, Jameson JL, Ito M (2002) Effects of aging on vasopressin production in a kindred with autosomal dominant neurohypophyseal diabetes insipidus due to the ΔE47 neurophysin mutation. The Journal of Clinical Endocrinology & Metabolism 87:870-876.Martin Valdearcos MMR, Daniel I. Benjamin, Daniel K. Nomura, Allison W. Xu (2014) Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function. Cell Report 24; 9(6): 2124–2138. .Mifflin SW, Strack A (2007) Obesity and the central nervous system. J Physiol 583:423.Molinoff PB AJ (1971) Biochemistry of catecholamines. Annu Rev Biochem.Moore AZ, Caturegli G, Metter EJ, Makrogiannis S, Resnick SM, Harris TB, Ferrucci L (2014) Difference in muscle quality over the adult life span and biological correlates in the Baltimore Longitudinal Study of Aging. Journal of the American Geriatrics Society 62:230-236.Morrison FG, Ressler KJ (2014) From the neurobiology of extinction to improved clinical treatments. Depression and anxiety 31:279-290.Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M (2012) Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One 7:e46057.Rosenbaum M, Leibel RL, Hirsch J (1997) Obesity. N Engl J Med 337:396-407.Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA (1996) The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97:1111-1116.Schummers J, Yu H, Sur M (2008) Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320:1638-1643.Shi H, Clegg DJ (2009) Sex differences in the regulation of body weight. Physiol Behav 97:199-204.Shi H, Strader AD, Woods SC, Seeley RJ (2007) The effect of fat removal on glucose tolerance is depot specific in male and female mice. American Journal of Physiology-Endocrinology and Metabolism 293:E1012-E1020.Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. Journal of visualized experiments: JoVE.Taylor AL, Fishman LM (1988) Corticotropin-releasing hormone. New England Journal of Medicine 319:213-222.Teske J, Billington C, Kotz C (2010) Hypocretin/orexin and energy expenditure. Acta physiologica 198:303-312.Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR (2012) Obesity is associated with hypothalamic injury in rodents and humans. The Journal of clinical investigation 122:153.Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9:2124-2138.Vale W, Rivier C, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245-270.Wee YS, Roundy KM, Weis JJ, Weis JH (2012) Interferon-inducible transmembrane proteins of the innate immune response act as membrane organizers by influencing clathrin and v-ATPase localization and function. Innate immunity 18:834-845.Wee YS, Weis JJ, Gahring LC, Rogers SW, Weis JH (2015) Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins. PLoS One 10:e0123218.Woods SC, Seeley RJ, Porte D, Schwartz MW (1998) Signals that regulate food intake and energy homeostasis. Science 280:1378-1383.Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, LeRoith D (2006) Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147:5826-5834.Yang L, Qi Y, Yang Y (2015) Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep 11:798-807.Yin Shen Wee JJW, Lorise C. Gahring, Scott W. Rogers, John H. Weis (2015) Age-Related Onset of Obesity Corresponds with Metabolic Dysregulation and Altered Microglia Morphology in Mice Deficient for Ifitm Proteins. In. PLoS ONE 10(4): e0123218. doi:10.1371/journal.pone.0123218.Zhang Z, Liu J, Li M, Yang H, Zhang C (2012) Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One 7:e49265.Ahima RS, Antwi DA (2008) Brain regulation of appetite and satiety. Endocrinology and metabolism clinics of North America 37:811-823.Anand BK, Brobeck JR (1951) Hypothalamic control of food intake in rats and cats. The Yale journal of biology and medicine 24:123.Anderberg RH, Richard JE, Hansson C, Nissbrandt H, Bergquist F, Skibicka KP (2016) GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality. Psychoneuroendocrinology 65:54-66.Anisman H, Zaharia MD, Meaney MJ, Merali Z (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci 16:149-164.Anisman H, Zaharia MD, Meaney MJ, Z. M (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci16(3–4):149–64.Aponte Y, Atasoy, D. & Sternson, S. M. (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci 14, 351–355.Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1-12.Arborelius L OM, Plotsky PM, Nemeroff CB. (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160(1):1–12.Bailey CC, Zhong G, Huang IC, Farzan M (2014) IFITM-Family Proteins: The Cell`s First Line of Antiviral Defense. Annu Rev Virol 1:261-283.Bailey CC KH, Huang IC, Farzan M (2013) Interferon-induced transmembrane protein 3 is a type II transmembrane protein. J Biol Chem 288:32184-93.Baláž M, Bočková M, Rektorová I, Rektor I (2011) Involvement of the subthalamic nucleus in cognitive functions—a concept. Journal of the neurological sciences 310:96-99.Bale TL VW (2004 ) CRF AND CRF R ECEPTORS:Role in Stress Responsivity and Other Behaviors. Annu Rev Pharmacol Toxicol Feb 10;44(1):525–57. .Barsh GS, Farooqi, I.S. & O`Rahilly, S. (2000) Genetics of body-weight regulation. . Nature 404, 644–651.Beaumont D, Waigh RD, Sunbhanich M, Nott MW (1983) Synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines and their actions at adrenoceptors in vivo and in vitro. J Med Chem 26:507-515.Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139:1243-1254.Bray GA, York DA (1979) Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiological Reviews 59:719-809.Butler AA (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. . Endocrinology 141, 3518–3521.Cai D YM, Frantz DF, Melendez PA, Hansen L, et al. ( 2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-βand NF-κB. . Nat Med 11:183–90.Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491-495.Chen YX, Welte K, Gebhard DH, Evans RL (1984) Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen. J Immunol 133:2496-2501.Chuang JC, Zigman JM (2010) Ghrelin`s Roles in Stress, Mood, and Anxiety Regulation. Int J Pept 2010.Coleman DL (1973) Effects of parabiosis of obese with diabetes and normal mice. . Diabetologia 9, 294–298 (1973) Coleman DLH, K.P. (1969) Effects of parabiosis of normal with genetically diabetic mice. Am. J. . Physiol 217, 1298–1304 (1969) Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci pp. 571-578.Czaja JA, Goy RW (1975) Ovarian hormones and food intake in female guinea pigs and rhesus monkeys. Hormones and Behavior 6:329-349.D. Atasoy JNB, H.H. Su, S.M. Sternson (2012) Deconstruction of a neural circuit for hunger. Nature 488 (2012), pp. 172-177.Dallman MF, Warne JP, Foster MT, Pecoraro NC (2007) Glucocorticoids and insulin both modulate caloric intake through actions on the brain. J Physiol 583:431-436.Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4-7.Danguir J, Nicolaidis S (1980) Intravenous infusions of nutrients and sleep in the rat: an ischymetric sleep regulation hypothesis. American Journal of Physiology-Endocrinology And Metabolism 238:E307-E312.Deblandre GA, Marinx OP, Evans SS, Majjaj S, Leo O, Caput D, Huez GA, Wathelet MG (1995) Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth. J Biol Chem 270:23860-23866.Deussing J CA, Dedic N ( 2017) The CRF family of neuropeptides and their receptors—mediators of the central stress response. Curr Mol Pharmacol Mar 2;10(999):1–1. .Diamond MS, Farzan M (2013) The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13:46-57.Dietrichs E (1984) Cerebellar autonomic function: direct hypothalamocerebellar pathway. Science 223:591-593.Dimond S (1978) Depletion of awareness and double-simultaneous stimulation in split-brain man. Cortex 14:604-607.DL C (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 9 9, 294–298 (1973).Donath MY B-SM, Ellingsgaard H, Halban PA, Ehses JA. (2010) Cytokine production by islets in health and diabetes: cellular origin, regulation and function. . Trends EndocrinolMetab 21:261-67.E.M. Parise NL, K. Kay, A.M. Dossat, R. Seth, J.M. Overton, D.L. Williams (2011) Evidence for the role of hindbrain orexin-1 receptors in the control of meal size. Am J Physiol Regul Integr Comp Physiol R1692-R1699.Eckel LA, Houpt TA, Geary N (2000) Spontaneous meal patterns in female rats with and without access to running wheels. Physiology & behavior 70:397-405.Ehses JA B-SM, Faulenbach M, Donath MY. (2008) Macrophages, cytokines and β-cell death in Type 2 diabetes. . Biochem Soc Trans 36:340–42.Emanuela F, Grazia M, Marco DR, Maria Paola L, Giorgio F, Marco B (2012) Inflammation as a link between obesity and metabolic syndrome. Journal of nutrition and metabolism 2012.Epstein H (1971) The origin of the domestic animals of Africa: Africana Publishing Corporation.Evans SS, Lee DB, Han T, Tomasi TB, Evans RL (1990) Monoclonal antibody to the interferon-inducible protein Leu-13 triggers aggregation and inhibits proliferation of leukemic B cells. Blood 76:2583-2593.Everitt AR, et al. (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484:519-523.Everitt BJ, Meister B, Hökfelt T, Melander T, Terenius L, Rökaeus Å, Theodorsson-Norheim E, Dockray G, Edwardson J, Cuello C (1986) The hypothalamic arcuate nucleus-median eminence complex: immunohistochemistry of transmitters, peptides and DARPP-32 with special reference to coexistence in dopamine neurons. Brain Research Reviews 11:97-155.Fang P-H, Yu M, Ma Y-P, Li J, Sui Y-M, Shi M-Y (2011) Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior. Neuroscience bulletin 27:407-412.Farooqi IS (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348, 1085–1095 (2003).Fonberg E (1969) The role of the hypothalamus and amygdala in food intake, alimentary motivation and emotional reactions. Acta Biol Exp 29:335-358.Fonberg E (1972) Control of emotional behaviour through the hypothalamus and amygdaloid complex. Physiology, emotion and psychosomatic illness:131-161.Ford ES (2005) Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome. Diabetes care 28:1769-1778.Frey M, Appenheimer MM, Evans SS (1997) Tyrosine kinase-dependent regulation of L-selectin expression through the Leu-13 signal transduction molecule: evidence for a protein kinase C-independent mechanism of L-selectin shedding. J Immunol 158:5424-5434.Friedman RL, Manly SP, McMahon M, Kerr IM, Stark GR (1984) Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38:745-755.G. A (1994) Regulation of pituitary ACTH secretion during chronic stress. Front Neuroendocrinol. 1994; 15(4):321–50.G.A. Bewick JVG, W.S. Dhillo, A.S. Kent, N.E. White, Z. Webster, M.A. Ghatei, S.R. Bloom (2005) Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J, 19, pp 1680-1682.Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N (2002) Removal of visceral fat prevents insulin resistance and glucose intolerance of aging. Diabetes 51:2951-2958.Garcia-Caceres C, et al. (2016) Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability. Cell 166:867-880.Gold PW, Gwirtsman H, Avgerinos PC, Nieman LK, Gallucci WT, Kaye W, Jimerson D, Ebert M, Rittmaster R, Loriaux DL (1986) Abnormal hypothalamic–pituitary–adrenal function in anorexia nervosa. New England Journal of Medicine 314:1335-1342.Gong EJ, Garrel D, Calloway DH (1989) Menstrual cycle and voluntary food intake. The American journal of clinical nutrition 49:252-258.Gray JM, Vecchiarelli HA, Morena M, Lee TT, Hermanson DJ, Kim AB, McLaughlin RJ, Hassan KI, Kühne C, Wotjak CT (2015) Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. Journal of Neuroscience 35:3879-3892.Graybiel AM, Rauch SL (2000) Toward a neurobiology of obsessive-compulsive disorder. Neuron 28:343-347.GS. H ( 2006) Inflammation and metabolic disorders. Nature 444:860–67.Hanagata N, Li X, Morita H, Takemura T, Li J, Minowa T (2011) Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. Journal of bone and mineral metabolism 29:279-290.Harrold JA, Dovey TM, Blundell JE, Halford JC (2012) CNS regulation of appetite. Neuropharmacology 63:3-17.Herman JP MJ, Ghosal S, Kopp B, Wulsin A, Makinson R (2016) Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. In: Comprehensive Physiology Hoboken, NJ, USA: John Wiley & Sons, Inc p. 603–21.Hetherington A, Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. American Journal of Physiology--Legacy Content 136:609-617.Hetherington A.W. and Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol 136, 609–617.Hong J, Stubbins RE, Smith RR, Harvey AE, Núñez NP (2009) Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutrition journal 8:11.Isaacson P (1982) Immunoperoxidase study of the secretory immunoglobulin system in colonic neoplasia. J Clin Pathol 35:14-25.J.E. Blevins MWS, D.G. Baskin (2004) Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol pp. R87-R96.J.N. Betley SX, Z.F. Cao, R. Gong, C.J. Magnus, Y. Yu, S.M. Sternson (2015) Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature, 521, pp 180-185.Jacobson L (2005) Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 34:271-292, vii.Jana M, Dasgupta S, Ghorpade A, Pahan K (2008) Astrocytes, oligodendrocytes, and Schwann cells. In: Neuroimmune Pharmacology, pp 69-88: Springer.Jia R, Pan Q, Ding S, Rong L, Liu SL, Geng Y, Qiao W, Liang C (2012) The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization. J Virol 86:13697-13707.Joëls M BTTn-sos (2009) The neuro-symphony of stress. Nat Rev Neurosci 2;10(6):459–66.Johnson RT, Breedlove SM, Jordan CL (2010) Astrocytes in the amygdala. Vitam Horm 82:23-45.Jun Chen ANE, Ying Liu (2012) Maternal deprivation in rats is associated with corticotropin releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol July ; 24(7): 1055–1064 doi:101111/j1365-2826201202306x.K. Rahmouni DAM (2007) Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension, 49, pp 647-652.Kalatzis V, Nevo N, Cherqui S, Gasnier B, Antignac C (2004) Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Hum Mol Genet 13:1361-1371.Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ (2000) Principles of neural science: McGraw-hill New York.Kevin W Williams JKE (2012) From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nature Neuroscience15,1350–1355(2012)doi:101038/nn3217.Koch M, Varela L, Kim JG, Kim JD, Hernandez-Nuno F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50.Koch M, Varela, L., Kim, J.G., Kim, J.D., Herna (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519,45–50.Koch M VL, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM6, Rakic P, Bechmann I, Cowley MA4, Szigeti-Buck K, Dietrich MO9, Gao XB, Diano S, Horvath TL (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 2015 Mar 5;519(7541):45-50 doi: 101038/nature14260 2015 Mar 5;519(7541):45-50. doi: 10.1038/nature14260.Krashes MJ (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121, 1424–1428 L. J (2005) Hypothalamic-pituitary-adrenocortical axis regulation. . Endocrinol Metab Clin North Am 2005; 34(2):271–92 vii.L.Horvath MJWT (2015) Neuronal Regulation of Energy Homeostasis: Beyond the Hypothalamus and Feeding. Cell Metabolism Volume 22, Issue 6.Lange UC, Saitou M, Western PS, Barton SC, Surani MA (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1.Lange UC, Adams DJ, Lee C, Barton S, Schneider R, Bradley A, Surani MA (2008) Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster. Mol Cell Biol 28:4688-4696.Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632-635.Lewin AR, Reid LE, McMahon M, Stark GR, Kerr IM (1991) Molecular analysis of a human interferon-inducible gene family. Eur J Biochem 199:417-423.Liang J, Matheson B, Kaye W, Boutelle K (2014) Neurocognitive correlates of obesity and obesity-related behaviors in children and adolescents. International journal of obesity (2005) 38:494.Lindemann M (1973) The limbic system, its relationship to autonomic regulations and emotions. Zeitschrift fur arztliche Fortbildung 67:322.Lladó I, Rodríguez‐Cuenca S, Pujol E, Monjo M, Estrany ME, Roca P, Palou A (2002) Gender effects on adrenergic receptor expression and lipolysis in white adipose tissue of rats. Obesity 10:296-305.Lopez M, Nogueiras R, Tena-Sempere M, Dieguez C (2016) Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat Rev Endocrinol 12:421-432.Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-2117.Lutter M, Nestler EJ (2009) Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr 139:629-632.M.A. Cowley RGS, S. Diano, M. Tschöp, N. Pronchuk, K.L. Grove, C.J. Strasburger, M. Bidlingmaier, M. Esterman, M.L. Heiman, et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron, 37, pp 649-661.Mahoney CP, Weinberger E, Bryant C, Ito M, Jameson JL, Ito M (2002) Effects of aging on vasopressin production in a kindred with autosomal dominant neurohypophyseal diabetes insipidus due to the ΔE47 neurophysin mutation. The Journal of Clinical Endocrinology & Metabolism 87:870-876.Marc Schneeberger RG, Marc Claret (2013) Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J Endocrinol February 220 T25-T46 Martin Valdearcos MMR, Daniel I. Benjamin, Daniel K. Nomura, Allison W. Xu (2014) Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function. Cell Report 24; 9(6): 2124–2138. .Mason BL, Wang Q, Zigman JM (2014) The central nervous system sites mediating the orexigenic actions of ghrelin. Annu Rev Physiol 76:519-533.Meyerson BJ (1979) Hypothalamic hormones and behaviour. Med Biol 57:69-83.Michal M. Poplawski JWM, Xue-Jun Yang, and Charles V. Mobbs (2011) Hypothalamic Responses to Fasting Indicate Metabolic Reprogramming Away from Glycolysis Toward Lipid Oxidation. Endocrinology Nov; 151(11): 5206–5217. .Mifflin SW, Strack A (2007) Obesity and the central nervous system. J Physiol 583:423.Miyake Y, Okamoto Y, Onoda K, Kurosaki M, Shirao N, Okamoto Y, Yamawaki S (2010) Brain activation during the perception of distorted body images in eating disorders. Psychiatry Res 181:183-192.Moffatt P, Gaumond MH, Salois P, Sellin K, Bessette MC, Godin É, de Oliveira PT, Atkins GJ, Nanci A, Thomas G (2008) Bril: a novel bone‐specific modulator of mineralization. Journal of Bone and Mineral Research 23:1497-1508.Molinoff PB AJ (1971) Biochemistry of catecholamines. Annu Rev Biochem.Moore AZ, Caturegli G, Metter EJ, Makrogiannis S, Resnick SM, Harris TB, Ferrucci L (2014) Difference in muscle quality over the adult life span and biological correlates in the Baltimore Longitudinal Study of Aging. Journal of the American Geriatrics Society 62:230-236.Morrison FG, Ressler KJ (2014) From the neurobiology of extinction to improved clinical treatments. Depression and anxiety 31:279-290.Moy S, Nadler J, Perez A, Barbaro R, Johns J, Magnuson T, Piven J, Crawley J (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic‐like behavior in mice. Genes, Brain and Behavior 3:287-302.Ozsoy S, Olguner Eker O, Abdulrezzak U (2016) The Effects of Antidepressants on Neuropeptide Y in Patients with Depression and Anxiety. Pharmacopsychiatry 49:26-31.P. Holzer FR, A. Farzi (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 46 (6), pp. 261-274.Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M (2012) Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One 7:e46057.Plotsky PM MME (1993) postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. . BrainRes Mol Brain Res 1993; 18(3):195–200.Razzoli M, Pearson C, Crow S, Bartolomucci A (2017) Stress, overeating, and obesity: Insights from human studies and preclinical models. Neuroscience & Biobehavioral Reviews.Regev L BT (2014 ) Corticotropin releasing factor in neuroplasticity. Front Neuroendocrinol. Front Neuroendocrinol Apr;35(2):171–9.Reid LE, Brasnett AH, Gilbert CS, Porter A, Gewert DR, Stark GR, Kerr IM (1989) A single DNA response element can confer inducibility by both alpha-and gamma-interferons. Proceedings of the National Academy of Sciences 86:840-844.Robinson GE, Grozinger CM, Whitfield CW (2005) Sociogenomics: social life in molecular terms. Nat Rev Genet 6:257-270.Rossi J (2011) Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. . Cell Metab 13, 195–204 (2011).S.M. Harlan DAM, K. Agassandian, D.F. Guo, M.D. Cassell, C.D. Sigmund, A.L. Mark, K. Rahmouni (2011) Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res, 108, pp 808-812.Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA (1996) The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97:1111-1116.Saper CB, Lowell BB (2014) The hypothalamus. Current Biology 24:R1111-R1116.Saper CB, Chou TC, Elmquist JK (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36:199-211.Sawchenko P, Swanson L (1985) Localization, colocalization, and plasticity of corticotropin-releasing factor immunoreactivity in rat brain. In: Federation proceedings, pp 221-227.Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481-485.Schulkin J (1991) The allure of salt. Psychobiology 19:116-121.Schummers J, Yu H, Sur M (2008) Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320:1638-1643.Shi H, Clegg DJ (2009) Sex differences in the regulation of body weight. Physiol Behav 97:199-204.Shi H, Strader AD, Woods SC, Seeley RJ (2007) The effect of fat removal on glucose tolerance is depot specific in male and female mice. American Journal of Physiology-Endocrinology and Metabolism 293:E1012-E1020.Stellar E (1954) The physiology of motivation. Psychological review 61:5.Stellar E, Epstein A (1991) Neuroendocrine factors in salt appetite. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 42:345-355.Sunyer B, Patil S, Höger H, Lubec G (2016) Barnes maze, a useful task to assess spatial reference memory in the mice. Protoc Exchange 2007. In.Sutton GM (2006) Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors. Endocrinology 147, 2183–2196.Swenson RS (2006) Review of clinical and functional neuroscience. Educational Review Manual in Neurology.Takahashi S, Doss C, Levy S, Levy R (1990) TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen. The Journal of Immunology 145:2207-2213.Tanaka SS, Matsui Y (2002) Developmentally regulated expression of mil-1 and mil-2, mouse interferon-induced transmembrane protein like genes, during formation and differentiation of primordial germ cells. Mech Dev 119 Suppl 1:S261-267.Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. Journal of visualized experiments: JoVE.Taylor AL, Fishman LM (1988) Corticotropin-releasing hormone. New England Journal of Medicine 319:213-222.Teitelbaum P, Epstein AN (1962) The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychological review 69:74.Teske J, Billington C, Kotz C (2010) Hypocretin/orexin and energy expenditure. Acta physiologica 198:303-312.Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR (2012) Obesity is associated with hypothalamic injury in rodents and humans. The Journal of clinical investigation 122:153.Todorov A, Harris LT, Fiske ST (2006) Toward socially inspired social neuroscience. Brain Res 1079:76-85.Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9:2124-2138.Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394-1397.Vale W, Rivier C, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245-270.Vale W RC, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J. (1983) Chemical and biological characterization of corticotropin releasing factor. . Recent Prog Horm Res1983:39245–70.Vale W SJ, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 18;213(4514):1394–7.Watts AG (2015) 60 YEARS OF NEUROENDOCRINOLOGY: The structure of the neuroendocrine hypothalamus: the neuroanatomical legacy of Geoffrey Harris. J Endocrinol 226:T25-39.Watts AG, Sanchez-Watts G (2002) Interactions between heterotypic stressors and corticosterone reveal integrative mechanisms for controlling corticotropin-releasing hormone gene expression in the rat paraventricular nucleus. Journal of Neuroscience 22:6282-6289.Wee YS, Roundy KM, Weis JJ, Weis JH (2012) Interferon-inducible transmembrane proteins of the innate immune response act as membrane organizers by influencing clathrin and v-ATPase localization and function. Innate immunity 18:834-845.Wee YS, Weis JJ, Gahring LC, Rogers SW, Weis JH (2015) Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins. PLoS One 10:e0123218.Weisberg SP MD, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. (2003) Obesity isassociated with macrophage accumulation in adipose tissue. . J Clin Investig 112:1796–808.Williams KW (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. . J Neurosci 30, 2472–2479.Williams KW, Scott, M.M. & Elmquist, J.K. (2011) Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network. Eur J Pharmacol 660, 2–12 (2011) Woods SC, Seeley RJ, Porte D, Schwartz MW (1998) Signals that regulate food intake and energy homeostasis. Science 280:1378-1383.Woods SC, Seeley, R.J., Porte, D. Jr. & Schwartz, M.W. S (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378-1383 (1998) Xu H BG, Yang Q, Tan G, Yang D, et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 112:1821–30.Y. Kuperman MW, J. Dine, K. Staikin, O. Golani, A. Ramot, T. Nahum, C. Kuhne, Y. Shemesh, W. Wurst, A. Harmelin, J.M. Deussing, M. Eder, A. Chen (2016) CRFR1 in AgRP neurons modulates sympathetic nervous system activity to adapt to cold stress and fasting. Cell Metab, 23, pp 1185-1199.Y.C. Shi JL, Z. Lin, H. Zhang, L. Zhai, G. Sperk, R. Heilbronn, M. Mietzsch, S. Weger, X.F. Huang, R.F. Enriquez, P.A. Baldock, L. Zhang, A. Sainsbury, H. Herzog, S. Lin (2013) Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab, 17, pp 236-248.Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, LeRoith D (2006) Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147:5826-5834.Yang L, Qi Y, Yang Y (2015) Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep 11:798-807.Yeo GSH, L.K. (2012) Unraveling the brain regulation of appetite: lessons from genetics. Nat. Neurosci. 15, xxx–yyy (2012). .Yin Shen Wee JJW, Lorise C. Gahring, Scott W. Rogers, John H. Weis (2015) Age-Related Onset of Obesity Corresponds with Metabolic Dysregulation and Altered Microglia Morphology in Mice Deficient for Ifitm Proteins. In. PLoS ONE 10(4): e0123218. doi:10.1371/journal.pone.0123218.Yount JS, Karssemeijer RA, Hang HC (2012) S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus. J Biol Chem 287:19631-19641.Zhang R, Asai M, Mahoney CE, Joachim M, Shen Y, Gunner G, Majzoub JA (2017) Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice. Mol Psychiatry 22:733-744.Zhang Y (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.Zhang Z, Liu J, Li M, Yang H, Zhang C (2012) Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One 7:e49265.Zigman JM, Elmquist JK (2003) Minireview: From anorexia to obesity--the yin and yang of body weight control. Endocrinology 144:3749-3756. 描述 碩士
國立政治大學
神經科學研究所
102754004資料來源 http://thesis.lib.nccu.edu.tw/record/#G1027540041 資料類型 thesis dc.contributor.advisor 陳紹寬 zh_TW dc.contributor.advisor Chen, Shau-Kawun en_US dc.contributor.author (Authors) 林万焜 zh_TW dc.contributor.author (Authors) Lin, Wan-Kun en_US dc.creator (作者) 林万焜 zh_TW dc.creator (作者) Lin, Wan-Kun en_US dc.date (日期) 2017 en_US dc.date.accessioned 2-Feb-2018 11:24:43 (UTC+8) - dc.date.available 2-Feb-2018 11:24:43 (UTC+8) - dc.date.issued (上傳時間) 2-Feb-2018 11:24:43 (UTC+8) - dc.identifier (Other Identifiers) G1027540041 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/115747 - dc.description (描述) 碩士 zh_TW dc.description (描述) 國立政治大學 zh_TW dc.description (描述) 神經科學研究所 zh_TW dc.description (描述) 102754004 zh_TW dc.description.abstract (摘要) Ifitm基因是一群可被干擾素刺激表現的基因，目前已知這些基因參與細胞對病毒的防禦，然而其生化特性及這些基因參與的其他生物功能並不清楚。將這些基因敲除後小鼠會產生過度攝食的行為並會造成肥胖，同時在下視丘中黑皮質素的前驅物POMC的表現量顯著降低，此發現表明破壞Ifitm基因可導致下視丘功能被破壞。然而由於代謝的調控並非只由下視丘控制，Ifitm基因是否直接參與下視丘的功能並不清楚。本研究卽是在探討Ifitm基因是否在下視丘的功能中扮演重要的角色。我們首先透過與下視丘功能有關的行為分析測試是否有其他下視丘功能被破壞的證據。我們發現在IFITM基因剔除公鼠，3-6個月開始出現過度攝食的行為與體重明顯增加；然而IFITM基因剔除母鼠在18個月後才出現同樣的表現型。IFITM基因剔除公鼠，在OFT與FST的行為測試中行動力下降，IFITM基因剔除母鼠卻有較多的活動；在公鼠與母鼠中焦慮均顯著增加。我們進一步測試這些剔除鼠的下視丘組織及神經胜肽的表現，在組織分析中並沒有發現組織結構異常。在神經胜肽的分析中IFITM基因剔除鼠的CRF的表現量增加，與IFITM基因剔除鼠的焦慮行為顯示相同趨勢。POMC表現的減少與CRF表現的上升顯示下視丘的功能紊亂。我們同時發現IFITM基因剔除鼠中微膠細胞數增加，以及位於下視丘的細胞本體的體積增加。另外IFITM基因剔除鼠中的細胞激素TNF-α與IL-1β在周邊血清中的增加表明此剔除鼠的下視丘產生發炎。本研究發現剔除IFITM基因會造成多項下視丘功能受到影響，並發現此突變鼠有下視丘發炎的現象。此下視丘發炎是否為下視丘功能破壞的主因，及IFITM基因剔除鼠的下視丘功能異常的細胞分子機制將會進一步被分析。 zh_TW dc.description.abstract (摘要) Ifitm genes are a group of interferon-inducible genes, best known for their antiviral roles. Their biological functions other than cellular antivirus and the biochemical properties of these proteins are not well-understand. Previously age-dependent hyperphagia and obesity were reported in IfitmDel mutant mice, in which 5 Ifitm genes were deleted. The levels of pro-opiomelanocortin (POMC) in hypothalamus of these mice were significantly reduced, suggesting that the hyperphagia phenotype of IfitmDel mutants is caused by defective central melanocortin signaling. In this study, we examine whether the hypothalamic dysfunctions are developed in these mutants. Whether hypothalamus associated behaviors are disrupted in IfitmDel mutants was first examined. We discovered that the hyperphagia and obesity phenotype in IfitmDel mutants are gender-dependent. These phenotypes in male mutants are detectable starting from 4-6 months of age, but not detected until one-year old in female mutants. Male mutants reveal the trends of decreased activities, while female mutants exhibit increased locomotor activity. Both gender develop anxiety-like phenotype. The behavioral abnormalities support the hypothesis of hypothalamic dysfunctions. As the Ifitm genes are expressed in various stage during development, the anatomy and the functions of the hypothalamus of these mutants were further tested. The histological analyses show no anatomical defects, neuron count differences and morphological alterations of neurons in IfitmDel mutant brains of both genders. These results indicate that these proteins are rather crucial for maintaining normal physiology in the developed central nervous system (CNS). The expression levels of neuropeptides related to stress response and anxiety or depression status, such as corticotrophin releasing factor (CRF), are altered in mutant hypothalamus. In contrast, Cell count and cell body size of microglia, whereas sera levels of pro-inflammatory cytokines, including TNF-α and IL-1β are elevated in IfitmDel mice, indicating hypothalamic inflammation and microglial activation phenotypes. The cellular mechanisms underlying the hypothalamic dysfunctions and the causative relationship of the hypothalamic inflammation with these phenotypes shall be further explored in the future studies. en_US dc.description.tableofcontents 中文摘要 IAbstract IITable of content IVAbbreviation 1Introduction 31 Interferon-inciduble-tsnsmembrance protein (IFITM) 31.1Type of IFITM protein and their roles 31.2 IFITM deletion mice phenotype link to Hyperphagia 61.3 Hyperphagia and eating disorder 71.3.1 Hypothalamus dysfunction and circuity 91.3.2 Regulation of feeding condition and its structure of Hypothalamus 111.3.3 Neuro circuity or endocrine regulation in hypothalamus of feeding behavior 131.4 Hypothalamus and associates differentially with animal behavior 141.4.1 The hypothalamus and limbic system related behavior 141.4.2 Anxiety disorders regulation by the hypothalamus 151.4.3 Motor control of the hypothalamus 161.5 Inflammation and obesity and metabolism disorder 171.5.1 Link inflammation state and hyperphagia to metabolism disorder 181.6 Rationale and experimental design in this study 18Material and Methods 242.1 Mice 242.2 Open field test (OFT) 242.3 Elevated Plus Maze test (EPM) 252.4 Tail Suspension Test (TST) 252.5 Forced Swimming Test (FST) 262.6 Barnes maze test (BM) 262.7 Social interaction test 272.8 Immunohistochemistry 282.9 Nissl staining 292.10 ELISA (enzyme-linked immunosorbent assay) 302.11 RNA extraction from hypothalamus, Real time PCR 31Result 333.1 Hyperphagia and weight gain in IfitmDel mice 33Figure 1. Hyperphagia and weight gain only in young IfitmDel male mice (3-6months) and old mice (after16 month) of both gender in IfitmDel mice 363.2 IfitmDel mice exhibit higher locomotor activity in open field test (OFT) 38Figure 2. IfitmDel mice exhibit higher locomotor activity in open field test (OFT) 403.3 IfitmDel mice reveal increased anxiety status in elevated plus maze (EPM) 41Figure 3. IfitmDel mice reveal increased anxiety status in elevated plus maze (EPM) 433.4 Male mice spent more immobility time in depression-like behavior test 44Figure 4. Male mice spent more immobility time in depression-like behavior test 453.5 Lower activity in first trail in learning and memory test of male mice on Barnes Maze test (BM) 46Figure 5. Lower activity in first trail in learning and memory BM test 483.6 No Differences in Social Behavior of IfitmDel mice 49Figure 6 No Differences in Social Behavior of IfitmDel mice 503.7 Histological and immunohistochemical analysis of brain in IfitmDel mice 51Figure 7. Histological analysis of brain defects in IfitmDel mice 56Coronal section form cerebrum to cerebellum 563.8 TH (Tyrosine hydroxylase) cell showed no difference in IfitmDel mice 56Figure 8. The production of the enzyme tyrosine hydroxylase (TH) 58Cell showed no different in IfitmDel mice. 583.9 QPCR (Quantitative real-time PCR validation) results measuring neuropeptide levels in IfitmDel mice. 58Figure 9 QPCR (Quantitative real-time PCR validation) result in IfitmDel mice 593.10 The activation status of microglia are changed in cortex, hypothalamus 60Figure 10. Increase in cortex and Basal ganglia of microglia numbers, cell body size in the hypothalamus 643.11 Astrocyte showed no obvious different 64Figure 11. Astrocyte show no obvious different in IfitmDel mice 663.12 inflammation 67Figure 12. Inflammation in periphery plasma cell and brain 69Summary of our findings 70Discussion 72 zh_TW dc.format.extent 21089079 bytes - dc.format.mimetype application/pdf - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G1027540041 en_US dc.subject (關鍵詞) IFITM基因剔除鼠 zh_TW dc.subject (關鍵詞) 下視丘發炎 zh_TW dc.subject (關鍵詞) 下視丘功能破壞 zh_TW dc.subject (關鍵詞) IfitmDel mice en_US dc.subject (關鍵詞) Hypothalamic inflammation en_US dc.subject (關鍵詞) Hypothalamic dysfunctions en_US dc.title (題名) IFITM基因剔除鼠之下視丘功能之缺失研究 zh_TW dc.title (題名) Study of hypothalamus dysfunctions in IfitmDel mutant mice en_US dc.type (資料類型) thesis en_US dc.relation.reference (參考文獻) Anand BK et al. (1951) Hypothalamic control of food intake in rats and cats. The Yale journal of biology and medicine 24:123.Anderberg RH et al. (2016) GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality. Psychoneuroendocrinology 65:54-66.Anisman H et al. (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci16(3–4):149–64.Aponte Y, Atasoy, D. & Sternson, S. M. (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci 14, 351–355.Arborelius L OM, Plotsky PM, Nemeroff CB. (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160(1):1–12.Bailey CC et al. (2014) IFITM-Family Proteins: The Cell`s First Line of Antiviral Defense. Annu Rev Virol 1:261-283.Bailey CC KH, Huang IC, Farzan M (2013) Interferon-induced transmembrane protein 3 is a type II transmembrane protein. J Biol Chem 288:32184-93.Bale TL VW (2004 ) CRF AND CRF R ECEPTORS:Role in Stress Responsivity and Other Behaviors. Annu Rev Pharmacol Toxicol Feb 10;44(1):525–57. .Barsh GS, Farooqi, I.S. & O`Rahilly, S. (2000) Genetics of body-weight regulation. . Nature 404, 644–651.Beaumont D et al. (1983) Synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines and their actions at adrenoceptors in vivo and in vitro. J Med Chem 26:507-515.Brass AL et al. (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139:1243-1254.Bray GA et al. (1979) Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiological Reviews 59:719-809.Butler AA (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. . Endocrinology 141, 3518–3521.Cai D YM, Frantz DF, Melendez PA, Hansen L, et al. ( 2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-βand NF-κB. . Nat Med 11:183–90.Chen YX et al. (1984) Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen. J Immunol 133:2496-2501.Chuang JC et al. (2010) Ghrelin`s Roles in Stress, Mood, and Anxiety Regulation. Int J Pept 2010.Coleman DL (1973) Effects of parabiosis of obese with diabetes and normal mice. . Diabetologia 9, 294–298 (1973) Coleman DLH, K.P. (1969) Effects of parabiosis of normal with genetically diabetic mice. Am. J. . Physiol 217, 1298–1304 (1969) Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci pp. 571-578.D. Atasoy JNB, H.H. Su, S.M. Sternson (2012) Deconstruction of a neural circuit for hunger. Nature 488 (2012), pp. 172-177.Dallman MF et al. (2007) Glucocorticoids and insulin both modulate caloric intake through actions on the brain. J Physiol 583:431-436.Dandona P et al. (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4-7.Danguir J et al. (1980) Intravenous infusions of nutrients and sleep in the rat: an ischymetric sleep regulation hypothesis. American Journal of Physiology-Endocrinology And Metabolism 238:E307-E312.Deblandre GA et al. (1995) Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth. J Biol Chem 270:23860-23866.Deussing J CA, Dedic N ( 2017) The CRF family of neuropeptides and their receptors—mediators of the central stress response. Curr Mol Pharmacol Mar 2;10(999):1–1. .Diamond MS et al. (2013) The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13:46-57.Dimond S (1978) Depletion of awareness and double-simultaneous stimulation in split-brain man. Cortex 14:604-607.Donath MY B-SM, Ellingsgaard H, Halban PA, Ehses JA. (2010) Cytokine production by islets in health and diabetes: cellular origin, regulation and function. . Trends EndocrinolMetab 21:261-67.E.M. Parise NL, K. Kay, A.M. Dossat, R. Seth, J.M. Overton, D.L. Williams (2011) Evidence for the role of hindbrain orexin-1 receptors in the control of meal size. Am J Physiol Regul Integr Comp Physiol R1692-R1699.Ehses JA B-SM, Faulenbach M, Donath MY. (2008) Macrophages, cytokines and β-cell death in Type 2 diabetes. . Biochem Soc Trans 36:340–42.Epstein H (1971) The origin of the domestic animals of Africa: Africana Publishing Corporation.Evans SS et al. (1990) Monoclonal antibody to the interferon-inducible protein Leu-13 triggers aggregation and inhibits proliferation of leukemic B cells. Blood 76:2583-2593.Everitt AR et al. (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484:519-523.Farooqi IS (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348, 1085–1095 (2003).Fonberg E (1969) The role of the hypothalamus and amygdala in food intake, alimentary motivation and emotional reactions. Acta Biol Exp 29:335-358.Fonberg E (1972) Control of emotional behaviour through the hypothalamus and amygdaloid complex. Physiology, emotion and psychosomatic illness:131-161.Frey M et al. (1997) Tyrosine kinase-dependent regulation of L-selectin expression through the Leu-13 signal transduction molecule: evidence for a protein kinase C-independent mechanism of L-selectin shedding. J Immunol 158:5424-5434.Friedman RL et al. (1984) Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38:745-755.G. A (1994) Regulation of pituitary ACTH secretion during chronic stress. Front Neuroendocrinol. 1994; 15(4):321–50.G.A. Bewick JVG, W.S. Dhillo, A.S. Kent, N.E. White, Z. Webster, M.A. Ghatei, S.R. Bloom (2005) Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J, 19, pp 1680-1682.Gold PW et al. (1986) Abnormal hypothalamic–pituitary–adrenal function in anorexia nervosa. New England Journal of Medicine 314:1335-1342.GS. H ( 2006) Inflammation and metabolic disorders. Nature 444:860–67.Hanagata N et al. (2011) Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. Journal of bone and mineral metabolism 29:279-290.Harrold JA et al. (2012) CNS regulation of appetite. Neuropharmacology 63:3-17.Herman JP MJ, Ghosal S, Kopp B, Wulsin A, Makinson R (2016) Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. In: Comprehensive Physiology Hoboken, NJ, USA: John Wiley & Sons, Inc p. 603–21.Isaacson P (1982) Immunoperoxidase study of the secretory immunoglobulin system in colonic neoplasia. J Clin Pathol 35:14-25.J.E. Blevins MWS, D.G. Baskin (2004) Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol pp. R87-R96.J.N. Betley SX, Z.F. Cao, R. Gong, C.J. Magnus, Y. Yu, S.M. Sternson (2015) Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature, 521, pp 180-185.Jia R et al. (2012) The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization. J Virol 86:13697-13707.Joëls M BTTn-sos (2009) The neuro-symphony of stress. Nat Rev Neurosci 2;10(6):459–66.Jun Chen ANE, Ying Liu (2012) Maternal deprivation in rats is associated with corticotropin releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol July ; 24(7): 1055–1064 doi:101111/j1365-2826201202306x.K. Rahmouni DAM (2007) Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension, 49, pp 647-652.Kalatzis V et al. (2004) Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Hum Mol Genet 13:1361-1371.Kandel ER et al. (2000) Principles of neural science: McGraw-hill New York.Kevin W Williams JKE (2012) From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nature Neuroscience15,1350–1355(2012)doi:101038/nn3217.Koch M et al. (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50.Koch M, Varela, L., Kim, J.G., Kim, J.D., Herna (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519,45–50.Koch M VL, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM6, Rakic P, Bechmann I, Cowley MA4, Szigeti-Buck K, Dietrich MO9, Gao XB, Diano S, Horvath TL (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 2015 Mar 5;519(7541):45-50 doi: 101038/nature14260 2015 Mar 5;519(7541):45-50. doi: 10.1038/nature14260.Krashes MJ (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121, 1424–1428 L. J (2005) Hypothalamic-pituitary-adrenocortical axis regulation. . Endocrinol Metab Clin North Am 2005; 34(2):271–92 vii.L.Horvath MJWT (2015) Neuronal Regulation of Energy Homeostasis: Beyond the Hypothalamus and Feeding. Cell Metabolism Volume 22, Issue 6.Lange UC et al. (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1.Lange UC et al. (2008) Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster. Mol Cell Biol 28:4688-4696.Lewin AR et al. (1991) Molecular analysis of a human interferon-inducible gene family. Eur J Biochem 199:417-423.Lindemann M (1973) The limbic system, its relationship to autonomic regulations and emotions. Zeitschrift fur arztliche Fortbildung 67:322.Lutter M et al. (2009) Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr 139:629-632.M.A. Cowley RGS, S. Diano, M. Tschöp, N. Pronchuk, K.L. Grove, C.J. Strasburger, M. Bidlingmaier, M. Esterman, M.L. Heiman, et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron, 37, pp 649-661.Marc Schneeberger RG, Marc Claret (2013) Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J Endocrinol February 220 T25-T46 Mason BL et al. (2014) The central nervous system sites mediating the orexigenic actions of ghrelin. Annu Rev Physiol 76:519-533.Meyerson BJ (1979) Hypothalamic hormones and behaviour. Med Biol 57:69-83.Mifflin SW et al. (2007) Obesity and the central nervous system. J Physiol 583:423.Miyake Y et al. (2010) Brain activation during the perception of distorted body images in eating disorders. Psychiatry Res 181:183-192.Moffatt P et al. (2008) Bril: a novel bone‐specific modulator of mineralization. Journal of Bone and Mineral Research 23:1497-1508.Ozsoy S et al. (2016) The Effects of Antidepressants on Neuropeptide Y in Patients with Depression and Anxiety. Pharmacopsychiatry 49:26-31.P. Holzer FR, A. Farzi (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 46 (6), pp. 261-274.Plotsky PM MME (1993) postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. . BrainRes Mol Brain Res 1993; 18(3):195–200.Razzoli M et al. (2017) Stress, overeating, and obesity: Insights from human studies and preclinical models. Neuroscience & Biobehavioral Reviews.Regev L BT (2014 ) Corticotropin releasing factor in neuroplasticity. Front Neuroendocrinol. Front Neuroendocrinol Apr;35(2):171–9.Reid LE et al. (1989) A single DNA response element can confer inducibility by both alpha-and gamma-interferons. Proceedings of the National Academy of Sciences 86:840-844.Rossi J (2011) Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. . Cell Metab 13, 195–204 (2011).S.M. Harlan DAM, K. Agassandian, D.F. Guo, M.D. Cassell, C.D. Sigmund, A.L. Mark, K. Rahmouni (2011) Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res, 108, pp 808-812.Saper CB et al. (2014) The hypothalamus. Current Biology 24:R1111-R1116.Saper CB et al. (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36:199-211.Schoggins JW et al. (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481-485.Schulkin J (1991) The allure of salt. Psychobiology 19:116-121.Stellar E (1954) The physiology of motivation. Psychological review 61:5.Stellar E et al. (1991) Neuroendocrine factors in salt appetite. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 42:345-355.Sutton GM (2006) Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors. Endocrinology 147, 2183–2196.Swenson RS (2006) Review of clinical and functional neuroscience. Educational Review Manual in Neurology.Takahashi S et al. (1990) TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen. The Journal of Immunology 145:2207-2213.Tanaka SS et al. (2002) Developmentally regulated expression of mil-1 and mil-2, mouse interferon-induced transmembrane protein like genes, during formation and differentiation of primordial germ cells. Mech Dev 119 Suppl 1:S261-267.Teitelbaum P et al. (1962) The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychological review 69:74.Vale W et al. (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394-1397.Vale W et al. (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245-270.Vale W RC, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J. (1983) Chemical and biological characterization of corticotropin releasing factor. . Recent Prog Horm Res1983:39245–70.Vale W SJ, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 18;213(4514):1394–7.Wee YS et al. (2012) Interferon-inducible transmembrane proteins of the innate immune response act as membrane organizers by influencing clathrin and v-ATPase localization and function. Innate immunity 18:834-845.Weisberg SP MD, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. (2003) Obesity isassociated with macrophage accumulation in adipose tissue. . J Clin Investig 112:1796–808.Williams KW (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. . J Neurosci 30, 2472–2479.Williams KW, Scott, M.M. & Elmquist, J.K. (2011) Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network. Eur J Pharmacol 660, 2–12 (2011) Woods SC et al. (1998) Signals that regulate food intake and energy homeostasis. Science 280:1378-1383.Woods SC, Seeley, R.J., Porte, D. Jr. & Schwartz, M.W. S (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378-1383 (1998) Xu H BG, Yang Q, Tan G, Yang D, et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 112:1821–30.Y. Kuperman MW, J. Dine, K. Staikin, O. Golani, A. Ramot, T. Nahum, C. Kuhne, Y. Shemesh, W. Wurst, A. Harmelin, J.M. Deussing, M. Eder, A. Chen (2016) CRFR1 in AgRP neurons modulates sympathetic nervous system activity to adapt to cold stress and fasting. Cell Metab, 23, pp 1185-1199.Y.C. Shi JL, Z. Lin, H. Zhang, L. Zhai, G. Sperk, R. Heilbronn, M. Mietzsch, S. Weger, X.F. Huang, R.F. Enriquez, P.A. Baldock, L. Zhang, A. Sainsbury, H. Herzog, S. Lin (2013) Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab, 17, pp 236-248.Yeo GSH, L.K. (2012) Unraveling the brain regulation of appetite: lessons from genetics. Nat. Neurosci. 15, xxx–yyy (2012). .Yin Shen Wee JJW, Lorise C. Gahring, Scott W. Rogers, John H. Weis (2015) Age-Related Onset of Obesity Corresponds with Metabolic Dysregulation and Altered Microglia Morphology in Mice Deficient for Ifitm Proteins. In. PLoS ONE 10(4): e0123218. doi:10.1371/journal.pone.0123218.Yount JS et al. (2012) S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus. J Biol Chem 287:19631-19641.Zhang Y (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.Zhang Z et al. (2012) Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One 7:e49265.Zigman JM et al. (2003) Minireview: From anorexia to obesity--the yin and yang of body weight control. Endocrinology 144:3749-3756.Moy S, Nadler J, Perez A, Barbaro R, Johns J, Magnuson T, Piven J, Crawley J (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic‐like behavior in mice. Genes, Brain and Behavior 3:287-302.Sunyer B, Patil S, Höger H, Lubec G (2016) Barnes maze, a useful task to assess spatial reference memory in the mice. Protoc Exchange 2007. In.Ahima RS, Antwi DA (2008) Brain regulation of appetite and satiety. Endocrinology and metabolism clinics of North America 37:811-823.Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491-495.Czaja JA, Goy RW (1975) Ovarian hormones and food intake in female guinea pigs and rhesus monkeys. Hormones and Behavior 6:329-349.Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4-7.Dietrichs E (1984) Cerebellar autonomic function: direct hypothalamocerebellar pathway. Science 223:591-593.DL C (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 9 9, 294–298 (1973).Eckel LA, Houpt TA, Geary N (2000) Spontaneous meal patterns in female rats with and without access to running wheels. Physiology & behavior 70:397-405.Emanuela F, Grazia M, Marco DR, Maria Paola L, Giorgio F, Marco B (2012) Inflammation as a link between obesity and metabolic syndrome. Journal of nutrition and metabolism 2012.Everitt AR, et al. (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484:519-523.Fang P-H, Yu M, Ma Y-P, Li J, Sui Y-M, Shi M-Y (2011) Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior. Neuroscience bulletin 27:407-412.Ford ES (2005) Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome. Diabetes care 28:1769-1778.Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N (2002) Removal of visceral fat prevents insulin resistance and glucose intolerance of aging. Diabetes 51:2951-2958.Garcia-Caceres C, et al. (2016) Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability. Cell 166:867-880.Gong EJ, Garrel D, Calloway DH (1989) Menstrual cycle and voluntary food intake. The American journal of clinical nutrition 49:252-258.Graybiel AM, Rauch SL (2000) Toward a neurobiology of obsessive-compulsive disorder. Neuron 28:343-347.Hetherington A, Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. American Journal of Physiology--Legacy Content 136:609-617.Hetherington A.W. and Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol 136, 609–617.Hong J, Stubbins RE, Smith RR, Harvey AE, Núñez NP (2009) Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutrition journal 8:11.Jacobson L (2005) Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 34:271-292, vii.Jana M, Dasgupta S, Ghorpade A, Pahan K (2008) Astrocytes, oligodendrocytes, and Schwann cells. In: Neuroimmune Pharmacology, pp 69-88: Springer.Johnson RT, Breedlove SM, Jordan CL (2010) Astrocytes in the amygdala. Vitam Horm 82:23-45.Lange UC, Saitou M, Western PS, Barton SC, Surani MA (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1.Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632-635.Liang J, Matheson B, Kaye W, Boutelle K (2014) Neurocognitive correlates of obesity and obesity-related behaviors in children and adolescents. International journal of obesity (2005) 38:494.Lladó I, Rodríguez‐Cuenca S, Pujol E, Monjo M, Estrany ME, Roca P, Palou A (2002) Gender effects on adrenergic receptor expression and lipolysis in white adipose tissue of rats. Obesity 10:296-305.Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-2117.Mahoney CP, Weinberger E, Bryant C, Ito M, Jameson JL, Ito M (2002) Effects of aging on vasopressin production in a kindred with autosomal dominant neurohypophyseal diabetes insipidus due to the ΔE47 neurophysin mutation. The Journal of Clinical Endocrinology & Metabolism 87:870-876.Martin Valdearcos MMR, Daniel I. Benjamin, Daniel K. Nomura, Allison W. Xu (2014) Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function. Cell Report 24; 9(6): 2124–2138. .Mifflin SW, Strack A (2007) Obesity and the central nervous system. J Physiol 583:423.Molinoff PB AJ (1971) Biochemistry of catecholamines. Annu Rev Biochem.Moore AZ, Caturegli G, Metter EJ, Makrogiannis S, Resnick SM, Harris TB, Ferrucci L (2014) Difference in muscle quality over the adult life span and biological correlates in the Baltimore Longitudinal Study of Aging. Journal of the American Geriatrics Society 62:230-236.Morrison FG, Ressler KJ (2014) From the neurobiology of extinction to improved clinical treatments. Depression and anxiety 31:279-290.Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M (2012) Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One 7:e46057.Rosenbaum M, Leibel RL, Hirsch J (1997) Obesity. N Engl J Med 337:396-407.Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA (1996) The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97:1111-1116.Schummers J, Yu H, Sur M (2008) Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320:1638-1643.Shi H, Clegg DJ (2009) Sex differences in the regulation of body weight. Physiol Behav 97:199-204.Shi H, Strader AD, Woods SC, Seeley RJ (2007) The effect of fat removal on glucose tolerance is depot specific in male and female mice. American Journal of Physiology-Endocrinology and Metabolism 293:E1012-E1020.Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. Journal of visualized experiments: JoVE.Taylor AL, Fishman LM (1988) Corticotropin-releasing hormone. New England Journal of Medicine 319:213-222.Teske J, Billington C, Kotz C (2010) Hypocretin/orexin and energy expenditure. Acta physiologica 198:303-312.Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR (2012) Obesity is associated with hypothalamic injury in rodents and humans. The Journal of clinical investigation 122:153.Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9:2124-2138.Vale W, Rivier C, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245-270.Wee YS, Roundy KM, Weis JJ, Weis JH (2012) Interferon-inducible transmembrane proteins of the innate immune response act as membrane organizers by influencing clathrin and v-ATPase localization and function. Innate immunity 18:834-845.Wee YS, Weis JJ, Gahring LC, Rogers SW, Weis JH (2015) Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins. PLoS One 10:e0123218.Woods SC, Seeley RJ, Porte D, Schwartz MW (1998) Signals that regulate food intake and energy homeostasis. Science 280:1378-1383.Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, LeRoith D (2006) Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147:5826-5834.Yang L, Qi Y, Yang Y (2015) Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep 11:798-807.Yin Shen Wee JJW, Lorise C. Gahring, Scott W. Rogers, John H. Weis (2015) Age-Related Onset of Obesity Corresponds with Metabolic Dysregulation and Altered Microglia Morphology in Mice Deficient for Ifitm Proteins. In. PLoS ONE 10(4): e0123218. doi:10.1371/journal.pone.0123218.Zhang Z, Liu J, Li M, Yang H, Zhang C (2012) Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One 7:e49265.Ahima RS, Antwi DA (2008) Brain regulation of appetite and satiety. Endocrinology and metabolism clinics of North America 37:811-823.Anand BK, Brobeck JR (1951) Hypothalamic control of food intake in rats and cats. The Yale journal of biology and medicine 24:123.Anderberg RH, Richard JE, Hansson C, Nissbrandt H, Bergquist F, Skibicka KP (2016) GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality. Psychoneuroendocrinology 65:54-66.Anisman H, Zaharia MD, Meaney MJ, Merali Z (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci 16:149-164.Anisman H, Zaharia MD, Meaney MJ, Z. M (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci16(3–4):149–64.Aponte Y, Atasoy, D. & Sternson, S. M. (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci 14, 351–355.Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1-12.Arborelius L OM, Plotsky PM, Nemeroff CB. (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160(1):1–12.Bailey CC, Zhong G, Huang IC, Farzan M (2014) IFITM-Family Proteins: The Cell`s First Line of Antiviral Defense. Annu Rev Virol 1:261-283.Bailey CC KH, Huang IC, Farzan M (2013) Interferon-induced transmembrane protein 3 is a type II transmembrane protein. J Biol Chem 288:32184-93.Baláž M, Bočková M, Rektorová I, Rektor I (2011) Involvement of the subthalamic nucleus in cognitive functions—a concept. Journal of the neurological sciences 310:96-99.Bale TL VW (2004 ) CRF AND CRF R ECEPTORS:Role in Stress Responsivity and Other Behaviors. Annu Rev Pharmacol Toxicol Feb 10;44(1):525–57. .Barsh GS, Farooqi, I.S. & O`Rahilly, S. (2000) Genetics of body-weight regulation. . Nature 404, 644–651.Beaumont D, Waigh RD, Sunbhanich M, Nott MW (1983) Synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines and their actions at adrenoceptors in vivo and in vitro. J Med Chem 26:507-515.Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139:1243-1254.Bray GA, York DA (1979) Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiological Reviews 59:719-809.Butler AA (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. . Endocrinology 141, 3518–3521.Cai D YM, Frantz DF, Melendez PA, Hansen L, et al. ( 2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-βand NF-κB. . Nat Med 11:183–90.Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491-495.Chen YX, Welte K, Gebhard DH, Evans RL (1984) Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen. J Immunol 133:2496-2501.Chuang JC, Zigman JM (2010) Ghrelin`s Roles in Stress, Mood, and Anxiety Regulation. Int J Pept 2010.Coleman DL (1973) Effects of parabiosis of obese with diabetes and normal mice. . Diabetologia 9, 294–298 (1973) Coleman DLH, K.P. (1969) Effects of parabiosis of normal with genetically diabetic mice. Am. J. . Physiol 217, 1298–1304 (1969) Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci pp. 571-578.Czaja JA, Goy RW (1975) Ovarian hormones and food intake in female guinea pigs and rhesus monkeys. Hormones and Behavior 6:329-349.D. Atasoy JNB, H.H. Su, S.M. Sternson (2012) Deconstruction of a neural circuit for hunger. Nature 488 (2012), pp. 172-177.Dallman MF, Warne JP, Foster MT, Pecoraro NC (2007) Glucocorticoids and insulin both modulate caloric intake through actions on the brain. J Physiol 583:431-436.Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4-7.Danguir J, Nicolaidis S (1980) Intravenous infusions of nutrients and sleep in the rat: an ischymetric sleep regulation hypothesis. American Journal of Physiology-Endocrinology And Metabolism 238:E307-E312.Deblandre GA, Marinx OP, Evans SS, Majjaj S, Leo O, Caput D, Huez GA, Wathelet MG (1995) Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth. J Biol Chem 270:23860-23866.Deussing J CA, Dedic N ( 2017) The CRF family of neuropeptides and their receptors—mediators of the central stress response. Curr Mol Pharmacol Mar 2;10(999):1–1. .Diamond MS, Farzan M (2013) The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13:46-57.Dietrichs E (1984) Cerebellar autonomic function: direct hypothalamocerebellar pathway. Science 223:591-593.Dimond S (1978) Depletion of awareness and double-simultaneous stimulation in split-brain man. Cortex 14:604-607.DL C (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 9 9, 294–298 (1973).Donath MY B-SM, Ellingsgaard H, Halban PA, Ehses JA. (2010) Cytokine production by islets in health and diabetes: cellular origin, regulation and function. . Trends EndocrinolMetab 21:261-67.E.M. Parise NL, K. Kay, A.M. Dossat, R. Seth, J.M. Overton, D.L. Williams (2011) Evidence for the role of hindbrain orexin-1 receptors in the control of meal size. Am J Physiol Regul Integr Comp Physiol R1692-R1699.Eckel LA, Houpt TA, Geary N (2000) Spontaneous meal patterns in female rats with and without access to running wheels. Physiology & behavior 70:397-405.Ehses JA B-SM, Faulenbach M, Donath MY. (2008) Macrophages, cytokines and β-cell death in Type 2 diabetes. . Biochem Soc Trans 36:340–42.Emanuela F, Grazia M, Marco DR, Maria Paola L, Giorgio F, Marco B (2012) Inflammation as a link between obesity and metabolic syndrome. Journal of nutrition and metabolism 2012.Epstein H (1971) The origin of the domestic animals of Africa: Africana Publishing Corporation.Evans SS, Lee DB, Han T, Tomasi TB, Evans RL (1990) Monoclonal antibody to the interferon-inducible protein Leu-13 triggers aggregation and inhibits proliferation of leukemic B cells. Blood 76:2583-2593.Everitt AR, et al. (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484:519-523.Everitt BJ, Meister B, Hökfelt T, Melander T, Terenius L, Rökaeus Å, Theodorsson-Norheim E, Dockray G, Edwardson J, Cuello C (1986) The hypothalamic arcuate nucleus-median eminence complex: immunohistochemistry of transmitters, peptides and DARPP-32 with special reference to coexistence in dopamine neurons. Brain Research Reviews 11:97-155.Fang P-H, Yu M, Ma Y-P, Li J, Sui Y-M, Shi M-Y (2011) Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior. Neuroscience bulletin 27:407-412.Farooqi IS (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348, 1085–1095 (2003).Fonberg E (1969) The role of the hypothalamus and amygdala in food intake, alimentary motivation and emotional reactions. Acta Biol Exp 29:335-358.Fonberg E (1972) Control of emotional behaviour through the hypothalamus and amygdaloid complex. Physiology, emotion and psychosomatic illness:131-161.Ford ES (2005) Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome. Diabetes care 28:1769-1778.Frey M, Appenheimer MM, Evans SS (1997) Tyrosine kinase-dependent regulation of L-selectin expression through the Leu-13 signal transduction molecule: evidence for a protein kinase C-independent mechanism of L-selectin shedding. J Immunol 158:5424-5434.Friedman RL, Manly SP, McMahon M, Kerr IM, Stark GR (1984) Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38:745-755.G. A (1994) Regulation of pituitary ACTH secretion during chronic stress. Front Neuroendocrinol. 1994; 15(4):321–50.G.A. Bewick JVG, W.S. Dhillo, A.S. Kent, N.E. White, Z. Webster, M.A. Ghatei, S.R. Bloom (2005) Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J, 19, pp 1680-1682.Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N (2002) Removal of visceral fat prevents insulin resistance and glucose intolerance of aging. Diabetes 51:2951-2958.Garcia-Caceres C, et al. (2016) Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability. Cell 166:867-880.Gold PW, Gwirtsman H, Avgerinos PC, Nieman LK, Gallucci WT, Kaye W, Jimerson D, Ebert M, Rittmaster R, Loriaux DL (1986) Abnormal hypothalamic–pituitary–adrenal function in anorexia nervosa. New England Journal of Medicine 314:1335-1342.Gong EJ, Garrel D, Calloway DH (1989) Menstrual cycle and voluntary food intake. The American journal of clinical nutrition 49:252-258.Gray JM, Vecchiarelli HA, Morena M, Lee TT, Hermanson DJ, Kim AB, McLaughlin RJ, Hassan KI, Kühne C, Wotjak CT (2015) Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. Journal of Neuroscience 35:3879-3892.Graybiel AM, Rauch SL (2000) Toward a neurobiology of obsessive-compulsive disorder. Neuron 28:343-347.GS. H ( 2006) Inflammation and metabolic disorders. Nature 444:860–67.Hanagata N, Li X, Morita H, Takemura T, Li J, Minowa T (2011) Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. Journal of bone and mineral metabolism 29:279-290.Harrold JA, Dovey TM, Blundell JE, Halford JC (2012) CNS regulation of appetite. Neuropharmacology 63:3-17.Herman JP MJ, Ghosal S, Kopp B, Wulsin A, Makinson R (2016) Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. In: Comprehensive Physiology Hoboken, NJ, USA: John Wiley & Sons, Inc p. 603–21.Hetherington A, Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. American Journal of Physiology--Legacy Content 136:609-617.Hetherington A.W. and Ranson SW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol 136, 609–617.Hong J, Stubbins RE, Smith RR, Harvey AE, Núñez NP (2009) Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutrition journal 8:11.Isaacson P (1982) Immunoperoxidase study of the secretory immunoglobulin system in colonic neoplasia. J Clin Pathol 35:14-25.J.E. Blevins MWS, D.G. Baskin (2004) Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol pp. R87-R96.J.N. Betley SX, Z.F. Cao, R. Gong, C.J. Magnus, Y. Yu, S.M. Sternson (2015) Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature, 521, pp 180-185.Jacobson L (2005) Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 34:271-292, vii.Jana M, Dasgupta S, Ghorpade A, Pahan K (2008) Astrocytes, oligodendrocytes, and Schwann cells. In: Neuroimmune Pharmacology, pp 69-88: Springer.Jia R, Pan Q, Ding S, Rong L, Liu SL, Geng Y, Qiao W, Liang C (2012) The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization. J Virol 86:13697-13707.Joëls M BTTn-sos (2009) The neuro-symphony of stress. Nat Rev Neurosci 2;10(6):459–66.Johnson RT, Breedlove SM, Jordan CL (2010) Astrocytes in the amygdala. Vitam Horm 82:23-45.Jun Chen ANE, Ying Liu (2012) Maternal deprivation in rats is associated with corticotropin releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol July ; 24(7): 1055–1064 doi:101111/j1365-2826201202306x.K. Rahmouni DAM (2007) Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension, 49, pp 647-652.Kalatzis V, Nevo N, Cherqui S, Gasnier B, Antignac C (2004) Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Hum Mol Genet 13:1361-1371.Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ (2000) Principles of neural science: McGraw-hill New York.Kevin W Williams JKE (2012) From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nature Neuroscience15,1350–1355(2012)doi:101038/nn3217.Koch M, Varela L, Kim JG, Kim JD, Hernandez-Nuno F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50.Koch M, Varela, L., Kim, J.G., Kim, J.D., Herna (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519,45–50.Koch M VL, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM6, Rakic P, Bechmann I, Cowley MA4, Szigeti-Buck K, Dietrich MO9, Gao XB, Diano S, Horvath TL (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 2015 Mar 5;519(7541):45-50 doi: 101038/nature14260 2015 Mar 5;519(7541):45-50. doi: 10.1038/nature14260.Krashes MJ (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121, 1424–1428 L. J (2005) Hypothalamic-pituitary-adrenocortical axis regulation. . Endocrinol Metab Clin North Am 2005; 34(2):271–92 vii.L.Horvath MJWT (2015) Neuronal Regulation of Energy Homeostasis: Beyond the Hypothalamus and Feeding. Cell Metabolism Volume 22, Issue 6.Lange UC, Saitou M, Western PS, Barton SC, Surani MA (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1.Lange UC, Adams DJ, Lee C, Barton S, Schneider R, Bradley A, Surani MA (2008) Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster. Mol Cell Biol 28:4688-4696.Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632-635.Lewin AR, Reid LE, McMahon M, Stark GR, Kerr IM (1991) Molecular analysis of a human interferon-inducible gene family. Eur J Biochem 199:417-423.Liang J, Matheson B, Kaye W, Boutelle K (2014) Neurocognitive correlates of obesity and obesity-related behaviors in children and adolescents. International journal of obesity (2005) 38:494.Lindemann M (1973) The limbic system, its relationship to autonomic regulations and emotions. Zeitschrift fur arztliche Fortbildung 67:322.Lladó I, Rodríguez‐Cuenca S, Pujol E, Monjo M, Estrany ME, Roca P, Palou A (2002) Gender effects on adrenergic receptor expression and lipolysis in white adipose tissue of rats. Obesity 10:296-305.Lopez M, Nogueiras R, Tena-Sempere M, Dieguez C (2016) Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat Rev Endocrinol 12:421-432.Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111-2117.Lutter M, Nestler EJ (2009) Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr 139:629-632.M.A. Cowley RGS, S. Diano, M. Tschöp, N. Pronchuk, K.L. Grove, C.J. Strasburger, M. Bidlingmaier, M. Esterman, M.L. Heiman, et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron, 37, pp 649-661.Mahoney CP, Weinberger E, Bryant C, Ito M, Jameson JL, Ito M (2002) Effects of aging on vasopressin production in a kindred with autosomal dominant neurohypophyseal diabetes insipidus due to the ΔE47 neurophysin mutation. The Journal of Clinical Endocrinology & Metabolism 87:870-876.Marc Schneeberger RG, Marc Claret (2013) Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J Endocrinol February 220 T25-T46 Martin Valdearcos MMR, Daniel I. Benjamin, Daniel K. Nomura, Allison W. Xu (2014) Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function. Cell Report 24; 9(6): 2124–2138. .Mason BL, Wang Q, Zigman JM (2014) The central nervous system sites mediating the orexigenic actions of ghrelin. Annu Rev Physiol 76:519-533.Meyerson BJ (1979) Hypothalamic hormones and behaviour. Med Biol 57:69-83.Michal M. Poplawski JWM, Xue-Jun Yang, and Charles V. Mobbs (2011) Hypothalamic Responses to Fasting Indicate Metabolic Reprogramming Away from Glycolysis Toward Lipid Oxidation. Endocrinology Nov; 151(11): 5206–5217. .Mifflin SW, Strack A (2007) Obesity and the central nervous system. J Physiol 583:423.Miyake Y, Okamoto Y, Onoda K, Kurosaki M, Shirao N, Okamoto Y, Yamawaki S (2010) Brain activation during the perception of distorted body images in eating disorders. Psychiatry Res 181:183-192.Moffatt P, Gaumond MH, Salois P, Sellin K, Bessette MC, Godin É, de Oliveira PT, Atkins GJ, Nanci A, Thomas G (2008) Bril: a novel bone‐specific modulator of mineralization. Journal of Bone and Mineral Research 23:1497-1508.Molinoff PB AJ (1971) Biochemistry of catecholamines. Annu Rev Biochem.Moore AZ, Caturegli G, Metter EJ, Makrogiannis S, Resnick SM, Harris TB, Ferrucci L (2014) Difference in muscle quality over the adult life span and biological correlates in the Baltimore Longitudinal Study of Aging. Journal of the American Geriatrics Society 62:230-236.Morrison FG, Ressler KJ (2014) From the neurobiology of extinction to improved clinical treatments. Depression and anxiety 31:279-290.Moy S, Nadler J, Perez A, Barbaro R, Johns J, Magnuson T, Piven J, Crawley J (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic‐like behavior in mice. Genes, Brain and Behavior 3:287-302.Ozsoy S, Olguner Eker O, Abdulrezzak U (2016) The Effects of Antidepressants on Neuropeptide Y in Patients with Depression and Anxiety. Pharmacopsychiatry 49:26-31.P. Holzer FR, A. Farzi (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 46 (6), pp. 261-274.Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M (2012) Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One 7:e46057.Plotsky PM MME (1993) postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. . BrainRes Mol Brain Res 1993; 18(3):195–200.Razzoli M, Pearson C, Crow S, Bartolomucci A (2017) Stress, overeating, and obesity: Insights from human studies and preclinical models. Neuroscience & Biobehavioral Reviews.Regev L BT (2014 ) Corticotropin releasing factor in neuroplasticity. Front Neuroendocrinol. Front Neuroendocrinol Apr;35(2):171–9.Reid LE, Brasnett AH, Gilbert CS, Porter A, Gewert DR, Stark GR, Kerr IM (1989) A single DNA response element can confer inducibility by both alpha-and gamma-interferons. Proceedings of the National Academy of Sciences 86:840-844.Robinson GE, Grozinger CM, Whitfield CW (2005) Sociogenomics: social life in molecular terms. Nat Rev Genet 6:257-270.Rossi J (2011) Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. . Cell Metab 13, 195–204 (2011).S.M. Harlan DAM, K. Agassandian, D.F. Guo, M.D. Cassell, C.D. Sigmund, A.L. Mark, K. Rahmouni (2011) Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res, 108, pp 808-812.Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA (1996) The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97:1111-1116.Saper CB, Lowell BB (2014) The hypothalamus. Current Biology 24:R1111-R1116.Saper CB, Chou TC, Elmquist JK (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36:199-211.Sawchenko P, Swanson L (1985) Localization, colocalization, and plasticity of corticotropin-releasing factor immunoreactivity in rat brain. In: Federation proceedings, pp 221-227.Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481-485.Schulkin J (1991) The allure of salt. Psychobiology 19:116-121.Schummers J, Yu H, Sur M (2008) Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320:1638-1643.Shi H, Clegg DJ (2009) Sex differences in the regulation of body weight. Physiol Behav 97:199-204.Shi H, Strader AD, Woods SC, Seeley RJ (2007) The effect of fat removal on glucose tolerance is depot specific in male and female mice. American Journal of Physiology-Endocrinology and Metabolism 293:E1012-E1020.Stellar E (1954) The physiology of motivation. Psychological review 61:5.Stellar E, Epstein A (1991) Neuroendocrine factors in salt appetite. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 42:345-355.Sunyer B, Patil S, Höger H, Lubec G (2016) Barnes maze, a useful task to assess spatial reference memory in the mice. Protoc Exchange 2007. In.Sutton GM (2006) Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors. Endocrinology 147, 2183–2196.Swenson RS (2006) Review of clinical and functional neuroscience. Educational Review Manual in Neurology.Takahashi S, Doss C, Levy S, Levy R (1990) TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen. The Journal of Immunology 145:2207-2213.Tanaka SS, Matsui Y (2002) Developmentally regulated expression of mil-1 and mil-2, mouse interferon-induced transmembrane protein like genes, during formation and differentiation of primordial germ cells. Mech Dev 119 Suppl 1:S261-267.Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. Journal of visualized experiments: JoVE.Taylor AL, Fishman LM (1988) Corticotropin-releasing hormone. New England Journal of Medicine 319:213-222.Teitelbaum P, Epstein AN (1962) The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychological review 69:74.Teske J, Billington C, Kotz C (2010) Hypocretin/orexin and energy expenditure. Acta physiologica 198:303-312.Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR (2012) Obesity is associated with hypothalamic injury in rodents and humans. The Journal of clinical investigation 122:153.Todorov A, Harris LT, Fiske ST (2006) Toward socially inspired social neuroscience. Brain Res 1079:76-85.Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9:2124-2138.Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394-1397.Vale W, Rivier C, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245-270.Vale W RC, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J. (1983) Chemical and biological characterization of corticotropin releasing factor. . Recent Prog Horm Res1983:39245–70.Vale W SJ, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 18;213(4514):1394–7.Watts AG (2015) 60 YEARS OF NEUROENDOCRINOLOGY: The structure of the neuroendocrine hypothalamus: the neuroanatomical legacy of Geoffrey Harris. J Endocrinol 226:T25-39.Watts AG, Sanchez-Watts G (2002) Interactions between heterotypic stressors and corticosterone reveal integrative mechanisms for controlling corticotropin-releasing hormone gene expression in the rat paraventricular nucleus. Journal of Neuroscience 22:6282-6289.Wee YS, Roundy KM, Weis JJ, Weis JH (2012) Interferon-inducible transmembrane proteins of the innate immune response act as membrane organizers by influencing clathrin and v-ATPase localization and function. Innate immunity 18:834-845.Wee YS, Weis JJ, Gahring LC, Rogers SW, Weis JH (2015) Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins. PLoS One 10:e0123218.Weisberg SP MD, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. (2003) Obesity isassociated with macrophage accumulation in adipose tissue. . J Clin Investig 112:1796–808.Williams KW (2010) Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. . J Neurosci 30, 2472–2479.Williams KW, Scott, M.M. & Elmquist, J.K. (2011) Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network. Eur J Pharmacol 660, 2–12 (2011) Woods SC, Seeley RJ, Porte D, Schwartz MW (1998) Signals that regulate food intake and energy homeostasis. Science 280:1378-1383.Woods SC, Seeley, R.J., Porte, D. Jr. & Schwartz, M.W. S (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378-1383 (1998) Xu H BG, Yang Q, Tan G, Yang D, et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 112:1821–30.Y. Kuperman MW, J. Dine, K. Staikin, O. Golani, A. Ramot, T. Nahum, C. Kuhne, Y. Shemesh, W. Wurst, A. Harmelin, J.M. Deussing, M. Eder, A. Chen (2016) CRFR1 in AgRP neurons modulates sympathetic nervous system activity to adapt to cold stress and fasting. Cell Metab, 23, pp 1185-1199.Y.C. Shi JL, Z. Lin, H. Zhang, L. Zhai, G. Sperk, R. Heilbronn, M. Mietzsch, S. Weger, X.F. Huang, R.F. Enriquez, P.A. Baldock, L. Zhang, A. Sainsbury, H. Herzog, S. Lin (2013) Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab, 17, pp 236-248.Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, LeRoith D (2006) Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147:5826-5834.Yang L, Qi Y, Yang Y (2015) Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep 11:798-807.Yeo GSH, L.K. (2012) Unraveling the brain regulation of appetite: lessons from genetics. Nat. Neurosci. 15, xxx–yyy (2012). .Yin Shen Wee JJW, Lorise C. Gahring, Scott W. Rogers, John H. Weis (2015) Age-Related Onset of Obesity Corresponds with Metabolic Dysregulation and Altered Microglia Morphology in Mice Deficient for Ifitm Proteins. In. PLoS ONE 10(4): e0123218. doi:10.1371/journal.pone.0123218.Yount JS, Karssemeijer RA, Hang HC (2012) S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus. J Biol Chem 287:19631-19641.Zhang R, Asai M, Mahoney CE, Joachim M, Shen Y, Gunner G, Majzoub JA (2017) Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice. Mol Psychiatry 22:733-744.Zhang Y (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.Zhang Z, Liu J, Li M, Yang H, Zhang C (2012) Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One 7:e49265.Zigman JM, Elmquist JK (2003) Minireview: From anorexia to obesity--the yin and yang of body weight control. Endocrinology 144:3749-3756. zh_TW
