Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis

The past decade has greatly increased our understanding and appreciation of the ability of the central nervous system (CNS) to regulate food intake and body weight. This was spearheaded by the discovery of key molecules regulating body weight homeostasis. It is now also apparent that the CNS, especially the hypothalamus, plays a primary role in directly regulating glucose homeostasis, independently of effects on body weight. These discoveries are important given the increasing incidences of obesity and type II diabetes in Western societies. In this article, we will highlight recent data from genetically modified mice. These data and other models have helped to dissect the CNS pathways regulating body weight and glucose homeostasis. Finally, although these studies have been illustrative, they also underscore our relative lack of knowledge and highlight the need for more definitive approaches to unravel the functional significance of these pathways. J. Comp. Neurol. 493:63–71, 2005. © 2005 Wiley‐Liss, Inc.

[1]  C. Saper,et al.  Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat , 2003, The Journal of comparative neurology.

[2]  M. Reitman,et al.  Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. , 2001, Diabetes.

[3]  A. McCall,et al.  Expression of Leptin Receptor Isoforms in Rat Brain Microvessels. , 1998, Endocrinology.

[4]  R. Steiner,et al.  Serotonergic neurons are targets for leptin in the monkey. , 2001, The Journal of clinical endocrinology and metabolism.

[5]  Central administration of oleic acid inhibits glucose production and food intake. , 2002, Diabetes.

[6]  M. Tschöp,et al.  Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. , 2001, European journal of endocrinology.

[7]  Victor J. Hruby,et al.  Role of melanocortinergic neurons in feeding and the agouti obesity syndrome , 1997, Nature.

[8]  Shiaoching Gong,et al.  A gene expression atlas of the central nervous system based on bacterial artificial chromosomes , 2003, Nature.

[9]  H. Grill,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake , 2022 .

[10]  T. Horvath,et al.  Minireview: ghrelin and the regulation of energy balance--a hypothalamic perspective. , 2001, Endocrinology.

[11]  A. McCall,et al.  Expression of leptin receptor isoforms in rat brain microvessels. , 1998, Endocrinology.

[12]  J. Bue-Valleskey,et al.  The role of neuropeptide Y in the antiobesity action of the obese gene product , 1995, Nature.

[13]  R. Dardennes,et al.  Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. , 2003, The Journal of clinical endocrinology and metabolism.

[14]  R. Palmiter,et al.  Response of melanocortin–4 receptor–deficient mice to anorectic and orexigenic peptides , 1999, Nature Genetics.

[15]  M. Reitman,et al.  Leptin-replacement therapy for lipodystrophy. , 2002, The New England journal of medicine.

[16]  J. Friedman,et al.  Selective deletion of leptin receptor in neurons leads to obesity. , 2001, The Journal of clinical investigation.

[17]  J. Elmquist,et al.  Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/en.2003-0241 Minireview: From Anorexia to Obesity—The Yin and Yang of Body Weight Control , 2022 .

[18]  C. Saper,et al.  Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Nakazato,et al.  Ghrelin is a growth-hormone-releasing acylated peptide from stomach , 1999, Nature.

[20]  J Dixon,et al.  Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36). , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Woods,et al.  Central nervous system control of food intake , 2000, Nature.

[22]  R. Seeley,et al.  Melanocortin receptors in leptin effects , 1997, Nature.

[23]  J. Elmquist,et al.  Rethinking the central causes of diabetes , 2003, Nature Medicine.

[24]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[25]  K. Moar,et al.  Association of leptin receptor (OB-Rb), NPY and GLP-1 gene expression in the ovine and murine brainstem , 1998, Regulatory Peptides.

[26]  E. Dellinger,et al.  Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. , 2002, The New England journal of medicine.

[27]  L. Rossetti,et al.  Central melanocortin receptors regulate insulin action. , 2001, The Journal of clinical investigation.

[28]  R. Cone,et al.  Independent and additive effects of central POMC and leptin pathways on murine obesity. , 1997, Science.

[29]  S. B. Evans,et al.  Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat , 2003, Brain Research.

[30]  C. Saper,et al.  From Lesions to Leptin Hypothalamic Control of Food Intake and Body Weight , 1999, Neuron.

[31]  Alexander S. Banks,et al.  STAT3 signalling is required for leptin regulation of energy balance but not reproduction , 2003, Nature.

[32]  C. Saper,et al.  Chemical characterization of leptin‐activated neurons in the rat brain , 2000, The Journal of comparative neurology.

[33]  N. Hoggard,et al.  Localization of leptin receptor mRNA and the long form splice variant (Ob‐Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization , 1996, FEBS letters.

[34]  C. Saper,et al.  The Need to Feed Homeostatic and Hedonic Control of Eating , 2002, Neuron.

[35]  M. Nakazato,et al.  A role for ghrelin in the central regulation of feeding , 2001, Nature.

[36]  R. Hammer,et al.  Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy , 1999, Nature.

[37]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[38]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[39]  H. Grill,et al.  The Neuroanatomical Axis for Control of Energy Balance , 2002, Frontiers in Neuroendocrinology.

[40]  C. Saper,et al.  Leptin activates neurons in ventrobasal hypothalamus and brainstem. , 1997, Endocrinology.

[41]  R. Steiner,et al.  Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. , 1997, Endocrinology.

[42]  M. Mortrud,et al.  Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Cone,et al.  The central melanocortin system can directly regulate serum insulin levels. , 2000, Endocrinology.

[44]  R. Seeley,et al.  Identification of targets of leptin action in rat hypothalamus. , 1996, The Journal of clinical investigation.

[45]  A. G. Roseberry,et al.  Neuropeptide Y-Mediated Inhibition of Proopiomelanocortin Neurons in the Arcuate Nucleus Shows Enhanced Desensitization in ob/ob Mice , 2004, Neuron.

[46]  T. Ludwig,et al.  The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. , 2005, Cell metabolism.

[47]  M. Schwartz,et al.  Progress in the search for neuronal mechanisms coupling type 2 diabetes to obesity. , 2001, The Journal of clinical investigation.

[48]  M. Mortrud,et al.  Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. , 1994, Molecular endocrinology.

[49]  M. Smith,et al.  Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels , 1997, Nature.

[50]  M. Tschöp,et al.  Ghrelin induces adiposity in rodents , 2000, Nature.

[51]  A. Prentice,et al.  Effects of recombinant leptin therapy in a child with congenital leptin deficiency. , 1999, The New England journal of medicine.

[52]  G. Barsh,et al.  Genetic approaches to studying energy balance: perception and integration , 2002, Nature Reviews Genetics.

[53]  R. Devos,et al.  Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. , 1995, Science.

[54]  M. Low,et al.  Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus , 2001, Nature.

[55]  Thomas M. Harris,et al.  Use of Laser-Capture Microdissection for the Identification of Marker Genes for the Ventromedial Hypothalamic Nucleus , 2005, The Journal of Neuroscience.

[56]  Nancy A. Jenkins,et al.  Recombineering: a powerful new tool for mouse functional genomics , 2001, Nature Reviews Genetics.

[57]  J. Flier,et al.  The Role of SOCS-3 in Leptin Signaling and Leptin Resistance* , 1999, The Journal of Biological Chemistry.

[58]  C. Saper,et al.  Leptin Activates Hypothalamic CART Neurons Projecting to the Spinal Cord , 1998, Neuron.

[59]  K. Moar,et al.  Localization of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain. , 1998, Endocrinology.

[60]  M. Schwartz,et al.  Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. , 2003, Endocrinology.

[61]  D. Chapelot,et al.  Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. , 2004, American journal of physiology. Endocrinology and metabolism.

[62]  R. Cone,et al.  Central melanocortins and the regulation of weight during acute and chronic disease. , 2001, Recent progress in hormone research.

[63]  A. Haqq,et al.  Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome. , 2003, The Journal of clinical endocrinology and metabolism.

[64]  A. G. Roseberry,et al.  Transgenic Mice Expressing Green Fluorescent Protein under the Control of the Melanocortin-4 Receptor Promoter , 2003, The Journal of Neuroscience.

[65]  R. Palmiter,et al.  Attenuation of the Obesity Syndrome of ob/ob Mice by the Loss of Neuropeptide Y , 1996, Science.

[66]  S. Woods,et al.  Leptin Increases Hypothalamic Pro-opiomelanocortin mRNA Expression in the Rostral Arcuate Nucleus , 1997, Diabetes.

[67]  Steven L. Cohen,et al.  Weight-reducing effects of the plasma protein encoded by the obese gene. , 1995, Science.

[68]  Bruce M. Spiegelman,et al.  Obesity and the Regulation of Energy Balance , 2001, Cell.

[69]  J. Bryan,et al.  Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis , 2005, Nature Medicine.

[70]  L. Tartaglia,et al.  The Leptin Receptor* , 1997, The Journal of Biological Chemistry.

[71]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

[72]  Rachel Jones Visual attention: Now you see it... , 2002, Nature Reviews Neuroscience.

[73]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[74]  D. Figlewicz,et al.  Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[75]  B. Wisse,et al.  A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. , 2001, Diabetes.

[76]  M. Schwartz,et al.  Elevated plasma ghrelin levels in Prader–Willi syndrome , 2002, Nature Medicine.

[77]  J. Flier Obesity Wars Molecular Progress Confronts an Expanding Epidemic , 2004, Cell.

[78]  Gary J. Schwartz,et al.  Hypothalamic KATP channels control hepatic glucose production , 2005, Nature.

[79]  Roberto Conti,et al.  Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production , 2003, Nature Medicine.

[80]  Y. Nomura,et al.  Brain stem is a direct target for leptin's action in the central nervous system. , 2002, Endocrinology.

[81]  B. Stoffel‐Wagner Neurosteroid metabolism in the human brain. , 2001, European journal of endocrinology.

[82]  Zhaohui Feng,et al.  Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats , 2002, Nature Neuroscience.

[83]  H. Akil,et al.  Evidence for two separate opiate peptide neuronal systems , 1978, Nature.

[84]  Clifford B Saper,et al.  Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area , 1999, Neuron.

[85]  C. Saper,et al.  Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain. , 2004, Diabetes.

[86]  G. Barsh,et al.  Is the energy homeostasis system inherently biased toward weight gain? , 2003, Diabetes.

[87]  Tim Cheetham,et al.  Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. , 2003, The New England journal of medicine.

[88]  A. Blanks,et al.  Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus , 2004, Nature Neuroscience.

[89]  R. Darnell,et al.  Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[90]  R. Cone,et al.  Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice , 1997, Cell.

[91]  J. Halaas,et al.  Leptin and the regulation of body weight in mammals , 1998, Nature.

[92]  W. Shimizu,et al.  Elevated Circulating Level of Ghrelin in Cachexia Associated With Chronic Heart Failure: Relationships Between Ghrelin and Anabolic/Catabolic Factors , 2001, Circulation.

[93]  J. Friedman,et al.  The function of leptin in nutrition, weight, and physiology. , 2002, Nutrition reviews.

[94]  C. Saper,et al.  Distributions of leptin receptor mRNA isoforms in the rat brain , 1998, The Journal of comparative neurology.

[95]  H. Grill,et al.  Hyperphagic effects of brainstem ghrelin administration. , 2003, Diabetes.

[96]  B. Lowell,et al.  Leptin Receptor Signaling in POMC Neurons Is Required for Normal Body Weight Homeostasis , 2004, Neuron.