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The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

Published online by Cambridge University Press:  28 February 2007

Gareth Williams ,
Joanne A. Harrold  and
David J. Cutler
Gareth Williams*
Affiliation:
Diabetes and Endocrinology Research Group, Department of Medicine, The University of Liverpool, Liverpool L69 3GA, UK
Joanne A. Harrold
Affiliation:
Diabetes and Endocrinology Research Group, Department of Medicine, The University of Liverpool, Liverpool L69 3GA, UK
David J. Cutler
Affiliation:
Diabetes and Endocrinology Research Group, Department of Medicine, The University of Liverpool, Liverpool L69 3GA, UK
*
*Corresponding author: Professor Gareth Williams, fax +44 (0)151 706 5797, email [email protected]
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Abstract

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The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of ‘feeding’ and ‘satiety’ centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY ‘feeding’ receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as α-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as ‘agouti’ protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.

Keywords

HypothalamusObesityNeuropeptide YMelanocortinsOrexinsLeptin
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 59 , Issue 3 , August 2000 , pp. 385 - 396
Copyright
Copyright © The Nutrition Society 2000

References

Banks, WA, Kastin, AJ, Huang, W, Jaspan, JB & Maness, LM (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305–311.CrossRefGoogle ScholarPubMed
Baskin, DG, Breininger, JF & Schwartz, MW (1999) Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes 48, 828–833.CrossRefGoogle ScholarPubMed
Beck, B & Richy, S (1999) Hypothalamic hypocretin/orexin and neuropeptide Y: Divergent interaction with energy depletion and leptin. Biochemical and Biophysical Research Communications 258, 119–122.CrossRefGoogle ScholarPubMed
Bernardis, LL & Bellinger, LL (1996) The lateral hypothalamic area revisited: Ingestion behavior. Neuroscience and Biobehavior Reviews 20, 189–287.CrossRefGoogle Scholar
Boston, BA, Blaydon, KM, Varnerin, J & Cone, RD (1997) Independent and additive effects of central POMC and leptin pathways on murine obesity. Science 278, 1641–1644.CrossRefGoogle ScholarPubMed
Broberger, C, de Lecea, L, Sutcliffe, JG & Hökfelt, T (1998a) Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to the neuropeptide Y and agouti gene-related protein systems. Journal of Comparative Neurology 402, 460–474.3.0.CO;2-S>CrossRefGoogle Scholar
Broberger, C, Johansen, J, Johansson, C, Schalling, M & Hökfelt, T (1998b) The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proceedings of the National Academy of Sciences USA 95, 15043–15048.CrossRefGoogle ScholarPubMed
Cai, X, Widdowson, PS, Harrold, J, Wilson, S, Buckingham, R, Arch, JRS, Tadayyon, M, Clapham, JC, Wilding, J & Williams, G (1999) Hypothalamic orexin expression: Modulation by blood glucose and feeding. Diabetes 48, 2132–2137.CrossRefGoogle ScholarPubMed
Chemelli, RM, Willie, JT, Sinton, CM, Elmquist, JK, Scammell, T, Lee, C, Richardson, JA, Williams, SC, Xiong, Y, Kisanuki, Y, Fitch, TE, Nakazato, M, Hammer, RE, Saper, CB & Yanagisawa, M (1999) Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation. Cell 98, 437–451.CrossRefGoogle ScholarPubMed
Chen, C-T, Dun, SL, Kwok, EH, Dun, NJ & Chang, J-K (1999) Orexin A-like immunoreactivity in the rat brain. Neuroscience Letters 260, 161–164.CrossRefGoogle ScholarPubMed
Cheung, CC, Clifton, DK & Steiner, RA (1997) Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138, 4489–4492.CrossRefGoogle ScholarPubMed
Chronwall, BM (1985) Anatomy and physiology of the neuroendocrine arcuate nucleus. Peptides 6, 1–11.CrossRefGoogle ScholarPubMed
Criscione, L, Rigollier, P, Batzl-Hartmann, C, Rueger, H, Stricker-Krongrad, A, Wyss, P, Brunner, L, Whitebread, S, Yamaguchi, Y, Gerald, C, Heurich, RO, Walker, MW, Chiesi, M, Schilling, W, Hofbauer, KG & Levens, N (1998) Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. Journal of Clinical Investigation 102, 2136–2145.CrossRefGoogle ScholarPubMed
Csiffary, A, Gorcs, TJ & Palkovits, M (1990) Neuropeptide Y innervation of ACTH-immunoreactive neurons in the ARC of rats: A correlated light and electron microscopic double immunolabeling study. Brain Research 506, 215–222.CrossRefGoogle Scholar
Cutler, DJ, Morris, R, Sheridhar, V, Wattam, TAK, Holmes, S, Patel, S, Arch, JRS, Wilson, S, Buckingham, RE, Evans, ML, Leslie, RA & Williams, G (1999) Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord. Peptides 20, 1455–1470.CrossRefGoogle ScholarPubMed
Dagerlind, A, Friberg, K, Bean, A & Hokfelt, T (1992) Sensitive mRNA detection using unfixed tissue: Combined radioactive and non-radioactive in situ hybrid histochemistry. Histochemistry 98, 39–49.CrossRefGoogle ScholarPubMed
Date, Y, Ueta, Y, Yamashita, H, Yamaguchi, H, Matsukura, S, Kangawa, K, Sakurai, T, Yanagisawa, M & Nakazato, M (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proceedings of the National Academy of Sciences USA 96, 748–753.CrossRefGoogle ScholarPubMed
de Lecea, L, Kilduff, TS, Peyron, C, Gao, X-B, Foye, PE, Danielson, PE, Fukuhara, C, Battenberg, ELF, Gautvik, VT, Bartlett, FS, Frankel, WN, van den Pol, AN, Bloom, FE, Gautvik, KM & Sutcliffe, JG (1998) The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences USA 95, 322–327.CrossRefGoogle ScholarPubMed
Dryden, S, Frankish, H, Wang, Q & Williams, G (1994) Neuropeptide Y and energy balance: One way ahead for the treatment of obesity. European Journal of Clinical Investigation 24, 293–308.CrossRefGoogle ScholarPubMed
Dryden, S, King, P, Pickavance, L, Doyle, P & Williams, G (1999) Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats. Clinical Science 96, 307–312.CrossRefGoogle ScholarPubMed
Dryden, S, King, P & Williams, G (2000) Neuropeptide Y and the regulation of energy homeostasis. Behavioral and Neuropsychological Review (In the Press).Google Scholar
Dyer, CJ, Touchette, KJ, Carroll, JA, Allee, GL & Matteri, RL (1999) Cloning of porcine prepro-orexin cDNA and effects of an intramuscular injection of synthetic porcine orexin-B on feed intake in young pigs. Domestic Animal Endocrinology 16, 145–148.CrossRefGoogle ScholarPubMed
Edwards, CMB, Abusnana, S, Sunter, D, Murphy, KG, Ghatei, MA & Bloom, SR (1999) The effect of the orexins on food intake: Comparison with neuropeptide Y, melanin-concentrating hormone and galanin. Journal of Endocrinology 160, R7-R12.CrossRefGoogle ScholarPubMed
Egawa, M, Yoshimatsu, H & Bray, GA (1991) Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue. American Journal of Physiology 260, R328-R334.Google ScholarPubMed
Elias, CF, Saper, CB, Maratos-Flier, E, Tritos, NA, Lee, C, Kelly, J, Tatro, JB, Hoffman, GE, Ollmann, MM, Barsh, GS, Sakurai, T, Yanagisawa, M & Elmquist, JK (1998) Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. Journal of Comparative Neurology 402, 442–459.3.0.CO;2-R>CrossRefGoogle ScholarPubMed
Elmquist, JK, Ahima, RS, Elias, CF, Flier, JS & Saper, CB (1998) Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proceedings of the National Academy of Sciences USA 95, 741–746.CrossRefGoogle ScholarPubMed
Erickson, JC, Clegg, KE & Palmiter, RD (1996a) Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415–421.CrossRefGoogle ScholarPubMed
Erickson, JC, Hollopeter, G & Palmiter, RD (1996b) Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274, 1704–1707.CrossRefGoogle Scholar
Fan, W, Boston, BA, Kesterson, RA, Hruby, VJ & Cone, RD (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168.CrossRefGoogle ScholarPubMed
Flynn, MC, Plata-Salaman, CR & Ffench-Mullen, JM (1999) Neuropeptide Y-related compounds and feeding. Physiology and Behavior 65, 901–905.CrossRefGoogle ScholarPubMed
Friedman, JM & Halaas, JL (1998) Leptin and the regulation of body weight in mammals. Nature 395, 763–770.CrossRefGoogle ScholarPubMed
Fuxe, K, Tinner, B, Caberlotto, L, Bunnemann, B & Agnati, LF (1997) NPY Y1 receptor like immunoreactivity exists in a subpopulation of beta-endorphin immunoreactive nerve cells in the arcuate nucleus: A double immunolabelling analysis in the rat. Neuroscience Letters 225, 49–52.CrossRefGoogle Scholar
Gerald, C, Walker, MW, Criscione, L, Gustafson, EL, Batzl-Hartmann, C, Smith, KE, Vaysse, P, Durkin, MM, Laz, TM, Linemeyer, DL, Schaffhauser, AO, Whiteshank, S, Hofbauer, KG, Taber, RI, Branchek, TA & Weinshank, RL (1996) A receptor subtype involved in neuropeptide Y-induced food intake. Nature 382, 168–171.CrossRefGoogle ScholarPubMed
Griffond, B, Risold, PY, Jacquemard, C, Colard, C & Fellmann, D (1999) Insulin-induced hypoglycemia increases preprohypocretin (orexin) mRNA in the rat lateral hypothalamic area. Neuroscience Letters 262, 77–80.CrossRefGoogle ScholarPubMed
Guan, XM, Yu, H, Trumbauer, M, Frazier, E, Van der Ploeg, LH & Chen, H (1998) Induction of neuropeptide Y expression in dorso-medial hypothalamus of diet-induced obese mice. NeuroReport 9, 3415–3419.CrossRefGoogle Scholar
Håkansson, M, de Lecea, L, Sutcliffe, JG, Yanagisawa, M & Meister, B (1999) Leptin receptor and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus. Journal of Neuroendocrinology 11, 653–663.Google Scholar
Halaas, JL, Boozer, C, Blair-West, J, Fidhausein, N, Denton, DA & Friedman, JM (1997) Physiological responses to long-term peripheral and central leptin infusion in lean and obese mice. Proceedings of the National Academy of Sciences USA 94, 8878–8883.CrossRefGoogle ScholarPubMed
Harrold, JA, Widdowson, PS & Williams, G (1999a) Altered energy balance causes selective changes in melanocortin-4 (MC4-R) but not melanocortin-3 (MC3-R) receptors in specific hypothalamic regions: Further evidence that MC4-R activation is a physiological inhibitor of feeding. Diabetes 48, 267–271.Google Scholar
Harrold, JA, Widdowson, PS & Williams, G (1999b) Changes in hypothalamic agouti-related peptide (AGRP), but not a-MSH or pro-opiomelanocortin concentrations in dietary-obese and food-restricted rats. Biochemical and Biophysical Research Communications 258, 574–577.Google Scholar
Haskell-Luevano, C, Chen, P, Li, C, Chang, K, Smith, MS, Cameron, JL & Cone, RD (1999) Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. Endocrinology 140, 1408–1415.Google Scholar
Haynes, AC, Jackson, B, Overend, P, Buckingham, RE, Wilson, S, Tadayyon, M & Arch, JRS (1999) Effects of single and chronic ICV administration of the orexins on feeding in the rat. Peptides 20, 1099–1105.CrossRefGoogle Scholar
Hill, JO & Peters, JC (1998) Environmental contributions to the obesity epidemic. Science 280, 1371–1373.CrossRefGoogle Scholar
Horvath, TL, Diano, S & van den Pol, AN (1999) Synaptic interaction between the hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: A novel circuit implicated in metabolic and endocrine regulations. Journal of Neuroscience 19, 1072–1087.CrossRefGoogle ScholarPubMed
Huszar, D, Lynch, CA, Fairchild-Huntress, V, Dunmore, JH, Fang, Q, Berkemeier, LR, Gu, W, Kesterson, RA, Boston, BA, Cone, RD, Smith, FJ, Campfield, LA, Burn, P & Lee, R (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141.CrossRefGoogle ScholarPubMed
Ida, T, Nakahara, K, Katayama, T, Murakami, N & Nakazato, M (1999) Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Research 821, 526–529.Google Scholar
Inui, A (1999) Neuropeptide Y feeding receptors: Are multiple subtypes involved? Trends in Pharmacological Sciences 20, 43–46.CrossRefGoogle ScholarPubMed
Jegou, S, Blasquez, C, Delbende, C, Bunel, DT & Vaundry, H (1993) Regulation of a-melanocyte-stimulating hormone release from hypothalamic neurons. Annals of the New York Academy of Sciences 680, 260–278.CrossRefGoogle Scholar
Kalra, SP, Dube, MG, Fournier, A & Kalra, PS (1991a) Structure-function analysis of stimulation of food intake by neuropeptide Y: Effect of receptor agonists. Physiology and Behavior 50, 5–9.CrossRefGoogle ScholarPubMed
Kalra, SP, Dube, MG, Sahu, A, Phelps, C & Kalra, PS (1991b) Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proceedings of the National Academy of Sciences USA 38, 10931–10935.CrossRefGoogle Scholar
Kesterson, RA, Huszar, D, Lynch, CA, Simerly, RB & Cone, RD (1997) Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. Molecular Endocrinology 11, 630–637.CrossRefGoogle ScholarPubMed
Kiefer, LL, Ittoop, OR, Bunce, K, Truesdale, AT, Willard, DH, Nichols, JS, Blanchard, SG, Mountjoy, K, Chen, WJ & Wilkison, WO (1997) Mutations in the carboxyl terminus of agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors. Biochemistry 36, 2084–2090.CrossRefGoogle Scholar
Krude, H, Biebermann, H, Luck, W, Horn, R, Brabant, G & Gruters, A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genetics 19, 155–157.CrossRefGoogle ScholarPubMed
Lin, L, Faraco, J, Li, R, Kadotani, H, Rogers, W, Lin, X, Qui, X, de Jong, PJ, Nishino, S & Mignot, E (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376.CrossRefGoogle ScholarPubMed
Lu, D, Willard, D, Patel, IR, Kadwell, S, Overton, L, Kost, T, Luther, M, Woychik, RP, Wilkison, WO & Cone, RD (1994) Agouti protein is an antagonist of the melanocyte stimulating-hormone receptor. Nature 371, 799–802.CrossRefGoogle ScholarPubMed
Lubkin, M & Stricker-Krongrad, A (1998) Independent feeding and metabolic actions of orexins in mice. Biochemical and Biophysical Research Communications 253, 241–245.CrossRefGoogle ScholarPubMed
McKibbin, PE, Cotton, SJ, McMillan, S, Holloway, B, Mayers, R, McCarthy, HD & Williams, G (1991) Altered neuropeptide Y concentrations in specific hypothalamic regions of obese (fa/fa) Zucker rats. Diabetes 40, 1423–1429.Google Scholar
Mizuno, TM, Kleopoulos, SP, Bergen, HT, Roberts, JL, Priest, CA & Mobbs, CV (1998) Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47, 294–297.CrossRefGoogle ScholarPubMed
Mondal, MS, Nakazato, M, Date, Y, Murakami, N, Yanagisawa, M & Matsukura, S (1999) Widespread distribution of orexin in rat brain and its regulation upon fasting. Biochemical and Biophysical Research Communications 256, 495–499.CrossRefGoogle ScholarPubMed
Moriguchi, T, Sakurai, T, Nambu, T, Yanagisawa, M & Goto, K (1999) Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia. Neuroscience Letters 264, 101–104.Google Scholar
Morris, BJ (1989) Neuronal localisation of neuropeptide Y gene expression in rat brain. Journal of Comparative Neurology 290, 358–368.CrossRefGoogle ScholarPubMed
Mountjoy, K, Mortrud, M, Low, M, Simerly, R & Cone, R (1994) Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Molecular Endocrinology 8, 1298–1308.Google ScholarPubMed
Nambu, T, Sakurai, T, Mizukami, K, Hosoya, Y, Yanagisawa, M & Goto, K (1999) Distribution of orexin neurons in the adult rat brain. Brain Research 827, 243–260.CrossRefGoogle ScholarPubMed
Ollmann, MM, Wilson, BD, Yang, Y-K, Kerns, JA, Chen, Y, Gantz, I & Barsh, GS (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138.CrossRefGoogle ScholarPubMed
Peyron, C, Tighe, DK, van den Pol, AN, de Lecea, L, Heller, HC, Sutcliffe, JG & Kilduff, TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. Journal of Neuroscience 18, 9996–10015.CrossRefGoogle ScholarPubMed
Phillips, MS, Liu, Q, Hammond, HA, Dugan, V, Hey, PJ, Caskey, CJ & Hess, JF (1996) Leptin receptor missense mutation in the fatty Zucker rat. Nature Genetics 13, 18–19.CrossRefGoogle ScholarPubMed
Pickavance, L, Dryden, S, Hopkins, D, Bing, C, Frankish, H, Wang, Q, Vernon, RG & Williams, G (1996) Relationships between hypothalamic neuropeptide Y and food intake in the lactating rat. Peptides 17, 577–582.CrossRefGoogle ScholarPubMed
Pu, S, Jain, MR, Kalra, PS & Kalra, SP (1998) Orexins, a novel family of hypothalamic neuropeptides, modulate pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner. Regulatory Peptides 78, 133–136.Google Scholar
Qu, D, Ludwig, DS, Gammeltoft, S, Piper, M, Pelleymounter, MA, Cullen, MJ, Mathes, WF, Przypek, J, Kanarek, R & Maratos-Flier, E (1996) A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380, 243–247.CrossRefGoogle ScholarPubMed
Risold, PY, Griffond, B, Kilduff, TS, Sutcliffe, JG & Fellmann, D (1999) Preprohypocretin (orexin) and prolactin-like immunoreactivity are coexpressed by neurons of the rat lateral hypothalamic area. Neuroscience Letters 259, 153–156.CrossRefGoogle ScholarPubMed
Roselli-Rehfuss, L, Mountjoy, KG, Robbins, LS, Mortrud, MT, Low, MJ, Tatro, JB, Entwistle, ML, Simerly, RB & Cone, RD (1993) Identification of a receptor for g melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proceedings of the National Academy of Sciences USA 90, 8856–8860.Google Scholar
Sakurai, T, Amemiya, A, Ishii, M, Matsuzaki, I, Chemelli, RM, Tanaka, H, Williams, SC, Richardson, JA, Kozlowski, GP, Wilson, S, Arch, JRS, Buckingham, RE, Haynes, AC, Carr, SA, Annan, RS, McNulty, DE, Liu, W-S, Terrett, JA, Elshourbagy, NA, Bergsma, DJ & Yanagisawa, M (1998) Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 192, 573–585.CrossRefGoogle Scholar
Sakurai, T, Moriguchi, T, Furuya, K, Kajiwara, N, Nakamura, T, Yanagisawa, M & Goto, K (1999) Structure and function of human prepro-orexin gene. Journal of Biological Chemistry 274, 17771–17776.Google Scholar
Samson, WK, Gosnell, B, Chang, J-K, Resch, ZT & Murphy, TC (1999) Cardiovascular regulatory actions of the hypocretins in brain. Brain Research 831, 248–253.Google Scholar
Sanacora, G, Kershaw, M, Finkelstein, JA & White, JD (1990) Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation. Endocrinology 127, 730–737.CrossRefGoogle ScholarPubMed
Satoh, N, Ogawa, Y, Katsuura, G, Tsuji, T, Masuzaki, H, Hiraoka, J, Okazaki, T, Tamaki, M, Hayase, M, Yoshimasa, Y, Nishi, S, Hosoda, K & Nakao, K (1997) Pathophysiological significance of the obese gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats: Evidence for the loss of its satiety effect in VMH-lesioned rats. Endocrinology 138, 947–954.CrossRefGoogle ScholarPubMed
Schaffauser, AO, Stricker-Krongrad, A, Brunner, L, Cumin, F, Gerald, C, Whitebread, S, Criscione, L & Hofbauer, KG (1997) Inhibition of food intake by neuropeptide Y Y5 receptor subtype antisense oligodeoxynucleotides. Diabetes 46, 1792–1798.Google Scholar
Schioth, HB, Muceniece, R, Mutulis, F, Bouifrouri, AA, Mutule, I & Wikberg, JES (1999) Further pharmacological characterisation of the selective melanocortin 4 receptor antagonist HS014: Comparison with SHU9119. Neuropeptides 33, 191–196.CrossRefGoogle ScholarPubMed
Schwartz, MW, Figlewicz, DP, Baskin, DG, Woods, SC & Porte, DJ (1992) Insulin in the brain: A hormonal regulator of energy balance. Endocrine Reviews 13, 387–414.Google Scholar
Schwartz, MW, Seeley, RJ, Woods, SC, Weigle, DS, Campfield, LA, Burn, P & Baskin, DG (1997) Leptin increases hypothalamic proopiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123.CrossRefGoogle ScholarPubMed
Seeley, RJ, Yagaloff, KA, Fisher, SL, Burn, P, Thiele, TE, van Dijk, G, Baskin, DG & Schwartz, MW (1997) Melanocortin receptors in leptin effects. Nature 390, 349.CrossRefGoogle ScholarPubMed
Shutter, JR, Graham, M, Kinsey, AC, Scully, S, Luthy, R & Stark, KL (1997) Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Development 11, 593–602.CrossRefGoogle ScholarPubMed
Siegel, JM (1999) Narcolepsy: A key role for hypocretins (orexins). Cell 98, 409–412.Google Scholar
Sindelar, DK, Marsh, DJ, Mystkowski, PM, Palmiler, R & Schwartz, W (1999) Attenuation of diabetic hyperphagia in neuropeptide Y deficient mice. Diabetes 48, Suppl. 1, A26.Google Scholar
Smith, MS (1993) Lactation alters neuropeptide-Y and proopiomelanocortin gene expression in the arcuate nucleus of the rat. Endocrinology 133, 1258–1265.Google Scholar
Stephens, TW, Basinski, M, Bristow, PK, Bue-Valleskey, JM, Burgett, SG, Craft, L, Hales, J, Hoffmann, J, Hsiung, HM, Kriauciunas, A, MacKeller, W, Rosteck, PR, Schoner, B, Smith, D, Tinsley, FC, Zhang, XY & Heiman, M (1995) The role of neuropeptide Y in the antiobesity actions of the obese gene product. Nature 377, 530–532.CrossRefGoogle ScholarPubMed
Sweet, DC, Levine, AS, Billington, CJ & Kotz, CM (1999) Feeding response to central orexins. Brain Research 821, 535–538.CrossRefGoogle ScholarPubMed
Taheri, S, Mahmoodi, M, Opacka-Juffry, J, Ghatei, MA & Bloom, SR (1999) Distribution and quantification of immunoreactive orexin A in rat tissues. FEBS Letters 457, 157–161.Google Scholar
Takahashi, N, Okumura, T, Yamada, H & Kohgo, Y (1999) Stimulation of gastric acid secretion by centrally administered orexin-A in conscious rats. Biochemical and Biophysical Research Communications 254, 623–627.CrossRefGoogle ScholarPubMed
Trivedi, P, Yu, H, MacNeil, DJ, Van der Ploeg, LHT & Guan, X-M (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Letters 438, 71–75.CrossRefGoogle ScholarPubMed
van den Pol, AN (1999) Hypothalamic hypocretin (orexin): Robust innervation of the spinal cord. Journal of Neuroscience 19, 3171–3182.Google Scholar
van den Pol, AN, Gao, X-B, Obrietan, K, Kilduff, TS & Belousov, AB (1998) Presynaptic and postsynaptic actions and modulation of neuroendocrine by a new hypothalamic peptide, hypocretin/ orexin. Journal of Neuroscience 19, 7962–7971.CrossRefGoogle Scholar
Vettor, R, Zarjevski, N, Cusin, I, Rohner-Jeanrenaud, F & Jeanrenaud, B (1994) Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats. Diabetologia 37, 1202–1208.CrossRefGoogle ScholarPubMed
Wang, Q, Bing, C, Al-Barazanji, K, Mossakowaska, DE, Wang, X-M, McBay, DL, Neville, WA, Taddayon, M, Pickavance, L, Dryden, S, Thomas, MEA, McHale, MT, Gloyer, IS, Wilson, S, Buckingham, R, Arch, JRS, Trayhurn, P & Williams, G (1997) Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat. Diabetes 46, 335–341.CrossRefGoogle ScholarPubMed
Widdowson, PS, Upton, R, Henderson, L, Buckingham, R, Wilson, S & Williams, G (1997) Reciprocal regional changes in brain NPY receptor density during dietary restriction and dietary-induced obesity in the rat. Brain Research 774, 1–10.Google Scholar
Wijker, M, Wszolek, ZK, Wolters, ECH, Rooimans, MA, Pals, G, Pfeiffer, RF, Lynch, T, Rodnitzky, RL, Wilhelmsen, KC & Arwert, F (1996) Localization of the gene for rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration to chromosome 17q21. Human Molecular Genetics 5, 151–154.Google Scholar
Wilding, JP, Gilbey, SG, Bailey, CJ, Batt, RA, Williams, G, Ghatei, MA & Bloom, SR (1993) Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse. Endocrinology 132, 1939–1944.CrossRefGoogle ScholarPubMed
Wilding, JP, Gilbey, SG, Mannan, M, Aslam, N, Ghatei, MA & Bloom, SR (1992) Increased neuropeptide Y content in individual hypothalamic nuclei, but not neuropeptide Y mRNA, in diet-induced obesity in rats. Journal of Endocrinology 132, 299–304.CrossRefGoogle Scholar
Wilhelmsen, KC, Lynch, T, Pavlou, E, Higgins, M & Hygaard, TG (1994) Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21–22. American Journal of Human Genetics 55, 1159–1165.Google ScholarPubMed
Woods, SC, Seeley, RJ, Porte, D & Schwartz, MW (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378–1382.CrossRefGoogle ScholarPubMed
Yamamoto, Y, Ueta, Y, Date, Y, Nakazato, M, Hara, Y, Serino, R, Nomura, M, Shibuya, I, Matsukura, S & Yamashita, H (1999) Down regulation of prepro-orexin gene expression in genetically obese mice. Molecular Brain Research 65, 14–22.Google Scholar
Yeo, GSH, Farooqi, S, Aminian, S, Halsall, DJ, Stanhope, RG & O'Rahilly, S (1998) A frameshift mutation in MC4-R associated with dominantly inherited human obesity. Nature Genetics 20, 111–112.CrossRefGoogle Scholar
Zoli, M, Torri, C, Ferrari, R, Jansson, A, Zini, I, Fuxe, K & Agnati, LF (1998) The emergence of the volume transmission concept. Brain Research Reviews 26, 136–147.CrossRefGoogle ScholarPubMed