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Interacting Appetite-Regulating Pathways in the Hypothalamic Regulation of Body Weight¹

Department of Neuroscience (S.P.K., S.P., B.X.), Department of Physiology (M.G.D., P.S.K.), and The University of Florida Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32610; and Department of Obstetrics and Gynecology (T.L.H.), Yale University School of Medicine, New Haven, Connecticut 06510

I. Introduction

II. Neuroanatomical Substrate for Appetite Regulation

A. Arcuate nucleus

B. Ventromedial nucleus and lateral hypothalamus

C. Dorsomedial nucleus

D. Paraventricular nucleus and perifornical hypothalamus

E. Suprachiasmatic nucleus and the timing device

F. Overview of the neuroanatomical substrate associated with appetite control

III. Orexigenic Signals

A. Neuropeptide Y

B. Galanin

C. Endogenous opioid peptides

D. Melanin-concentrating hormone

E. Amino acids: glutamate and -aminobutyric acid

F. Hypocretins/orexins

G. Morphological and functional links among orexigenic signals

IV. Anorexigenic Signals

A. Corticotropin-releasing hormone family of peptides

B. Neurotensin

C. Glucagon-like peptide-1

D. Melanocortin and agouti protein

E. Cocaine and amphetamine-regulated transcript

V. Leptin

A. An adipocyte signal

B. Site of action

C. Is leptin a physiological satiety signal?

D. Leptin signal transduction and leptin resistance

VI. Summary

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				R. Nogueiras, S. Tovar, S. E. Mitchell, D. V. Rayner, Z. A. Archer, C. Dieguez, and L. M. Williams Regulation of Growth Hormone Secretagogue Receptor Gene Expression in the Arcuate Nuclei of the Rat by Leptin and Ghrelin Diabetes, October 1, 2004; 53(10): 2552 - 2558. [Abstract] [Full Text] [PDF]

				N. Ueno, M. G. Dube, A. Inui, P. S. Kalra, and S. P. Kalra Leptin Modulates Orexigenic Effects of Ghrelin and Attenuates Adiponectin and Insulin Levels and Selectively the Dark-Phase Feeding as Revealed by Central Leptin Gene Therapy Endocrinology, September 1, 2004; 145(9): 4176 - 4184. [Abstract] [Full Text] [PDF]

				C. Perrin, C. Knauf, and R. Burcelin Intracerebroventricular Infusion of Glucose, Insulin, and the Adenosine Monophosphate-Activated Kinase Activator, 5-Aminoimidazole-4-Carboxamide-1-{beta}-D-Ribofuranoside, Controls Muscle Glycogen Synthesis Endocrinology, September 1, 2004; 145(9): 4025 - 4033. [Abstract] [Full Text] [PDF]

				K.G. Murphy and S.R. Bloom Gut hormones in the control of appetite Exp Physiol, September 1, 2004; 89(5): 507 - 516. [Abstract] [Full Text] [PDF]

				T. Karl, S. Lin, C. Schwarzer, A. Sainsbury, M. Couzens, W. Wittmann, D. Boey, S. von Horsten, and H. Herzog Y1 receptors regulate aggressive behavior by modulating serotonin pathways PNAS, August 24, 2004; 101(34): 12742 - 12747. [Abstract] [Full Text] [PDF]

				D. Burdakov Electrical Signaling in Central Orexin/Hypocretin Circuits: Tuning Arousal and Appetite to Fit the Environment Neuroscientist, August 1, 2004; 10(4): 286 - 291. [Abstract] [PDF]

				N. Yasuda, T. Inoue, T. Nagakura, K. Yamazaki, K. Kira, T. Saeki, and I. Tanaka Metformin Causes Reduction of Food Intake and Body Weight Gain and Improvement of Glucose Intolerance in Combination with Dipeptidyl Peptidase IV Inhibitor in Zucker fa/fa Rats J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 614 - 619. [Abstract] [Full Text] [PDF]

				J. D. Coppola, B. A. Horwitz, J. Hamilton, and R. B. McDonald Expression of NPY Y1 and Y5 receptors in the hypothalamic paraventricular nucleus of aged Fischer 344 rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R69 - R75. [Abstract] [Full Text] [PDF]

				A. J. van der Lely, M. Tschop, M. L. Heiman, and E. Ghigo Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin Endocr. Rev., June 1, 2004; 25(3): 426 - 457. [Abstract] [Full Text] [PDF]

				J. Erdmann, R. Topsch, F. Lippl, P. Gussmann, and V. Schusdziarra Postprandial Response of Plasma Ghrelin Levels to Various Test Meals in Relation to Food Intake, Plasma Insulin, and Glucose J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3048 - 3054. [Abstract] [Full Text] [PDF]

				T. L. Horvath, S. Diano, and M. Tschop Brain Circuits Regulating Energy Homeostasis Neuroscientist, June 1, 2004; 10(3): 235 - 246. [Abstract] [PDF]

				M. R. Druce, C. J. Small, and S. R. Bloom Minireview: Gut Peptides Regulating Satiety Endocrinology, June 1, 2004; 145(6): 2660 - 2665. [Abstract] [Full Text] [PDF]

				A. Sahu Minireview: A Hypothalamic Role in Energy Balance with Special Emphasis on Leptin Endocrinology, June 1, 2004; 145(6): 2613 - 2620. [Abstract] [Full Text] [PDF]

				A. Schmidt, B. Marescau, E. A. Boehm, W. K. J. Renema, R. Peco, A. Das, R. Steinfeld, S. Chan, J. Wallis, M. Davidoff, et al. Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency Hum. Mol. Genet., May 1, 2004; 13(9): 905 - 921. [Abstract] [Full Text] [PDF]

				J. G. Hohmann, D. N. Teklemichael, D. Weinshenker, D. Wynick, D. K. Clifton, and R. A. Steiner Obesity and Endocrine Dysfunction in Mice with Deletions of both Neuropeptide Y and Galanin Mol. Cell. Biol., April 1, 2004; 24(7): 2978 - 2985. [Abstract] [Full Text] [PDF]

				A. P. Goldstone, E. L. Thomas, A. E. Brynes, G. Castroman, R. Edwards, M. A. Ghatei, G. Frost, A. J. Holland, A. B. Grossman, M. Korbonits, et al. Elevated Fasting Plasma Ghrelin in Prader-Willi Syndrome Adults Is Not Solely Explained by Their Reduced Visceral Adiposity and Insulin Resistance J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1718 - 1726. [Abstract] [Full Text] [PDF]

				E. Karteris, J. Chen, and H. S. Randeva Expression of Human Prepro-Orexin and Signaling Characteristics of Orexin Receptors in the Male Reproductive System J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1957 - 1962. [Abstract] [Full Text] [PDF]

				M. A. El-Haddad, M. Desai, D. Gayle, and M. G. Ross In Utero Development of Fetal Thirst and Appetite: Potential for Programming Reproductive Sciences, April 1, 2004; 11(3): 123 - 130. [Abstract] [PDF]

				K. Kiwaki, C. M. Kotz, C. Wang, L. Lanningham-Foster, and J. A. Levine Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E551 - E559. [Abstract] [Full Text] [PDF]

				A. INUI, A. ASAKAWA, C. Y. BOWERS, G. MANTOVANI, A. LAVIANO, M. M. MEGUID, and M. FUJIMIYA Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ FASEB J, March 1, 2004; 18(3): 439 - 456. [Abstract] [Full Text] [PDF]

				S. Fahrenkrog, T. Harder, E. Stolaczyk, K. Melchior, K. Franke, J. W. Dudenhausen, and A. Plagemann Cross-Fostering to Diabetic Rat Dams Affects Early Development of Mediobasal Hypothalamic Nuclei Regulating Food Intake, Body Weight, and Metabolism J. Nutr., March 1, 2004; 134(3): 648 - 654. [Abstract] [Full Text] [PDF]

				R. Burcelin, M. Uldry, M. Foretz, C. Perrin, A. Dacosta, M. Nenniger-Tosato, J. Seydoux, S. Cotecchia, and B. Thorens Impaired Glucose Homeostasis in Mice Lacking the {alpha}1b-Adrenergic Receptor Subtype J. Biol. Chem., January 9, 2004; 279(2): 1108 - 1115. [Abstract] [Full Text] [PDF]

				W. L. Peacock, E. Krol, K. M. Moar, J. S. McLaren, J. G. Mercer, and J. R. Speakman Photoperiodic effects on body mass, energy balance and hypothalamic gene expression in the bank vole J. Exp. Biol., January 1, 2004; 207(1): 165 - 177. [Abstract] [Full Text] [PDF]

				P. D. Raposinho, T. Pedrazzini, R. B. White, R. D. Palmiter, and M. L. Aubert Chronic Neuropeptide Y Infusion into the Lateral Ventricle Induces Sustained Feeding and Obesity in Mice Lacking Either Npy1r or Npy5r Expression Endocrinology, January 1, 2004; 145(1): 304 - 310. [Abstract] [Full Text] [PDF]

				A. Randich, P. C. Chandler, H. C. Mebane, M. E. Turnbach, S. T. Meller, G. R. Kelm, and J. E. Cox Jejunal administration of linoleic acid increases activity of neurons in the paraventricular nucleus of the hypothalamus Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2004; 286(1): R166 - R173. [Abstract] [Full Text] [PDF]