Appetite Control and Reproduction: Leptin and Beyond

 

 Buy Article Permissions and Reprints

ABSTRACT

It is now recognized that appropriate regulation of reproduction, energy intake, and energy expenditure, and thus maintenance of body weight and fertility, relies on complex hypothalamic neurocircuitry. Feeding and reproductive function are closely linked. During times of undernourishment and falling body fat the reproductive axis is down-regulated. Circulating factors and hypothalamic circuits coordinate these responses. Leptin has been described to be an important peripheral signal that indicates body fat stores to the hypothalamus and thus links nutrition and reproduction. Leptin acts by altering neuropeptide circuits in the hypothalamus, which alter gonadotropin-releasing hormone release and food intake. The importance of key neuropeptide systems identified in rodents is now being established in man. Notably mutations in the melanocortin MC4 receptor are found in up to 4% of the morbidly obese, and in a proportion of patients with anorexia nervosa mutations have been identified in the agouti-related peptide gene (AgRP), which codes for an endogenous antagonist of this receptor. Intranasal administration of a melanocortin fragment known to activate the MC4 receptor decreases adiposity in humans. The melanocortin system has been shown to influence the reproductive axis in rodents. However, the role of the melanocortin system in the control of reproduction in humans remains to be established. Since the discovery of leptin, attention has also been focused on peripheral signals that regulate reproduction, food intake, and energy expenditure, either directly or via feedback on hypothalamic circuits. Notable new discoveries in this area include the gastric hormone ghrelin. Circulating ghrelin stimulates food intake in rodents and humans, although an influence on the reproductive axis is yet to be reported.

REFERENCES

• 1 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature . 1994;  372 425-432
  CrossrefPubMedGoogle Scholar
• 2 Considine R V, Sinha M K, Heiman M L. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.  N Engl J Med . 1996;  334 292-295
  CrossrefPubMedGoogle Scholar
• 3 Schwartz M W, Peskind E, Raskind M, Boyko E J, Porte D. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans.  Nat Med . 1996;  2 589-593
  PubMedGoogle Scholar
• 4 Hoggard N, Mercer J G, Rayner D V, Moar K, Trayhurn P, Williams L M. Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization.  Biochem Biophys Res Commun . 1997;  232 383-387
  CrossrefPubMedGoogle Scholar
• 5 Elmquist J K, Bjorbaek C, Ahima R S, Flier J S, Saper C B. Distributions of leptin receptor mRNA isoforms in the rat brain.  J Comp Neurol . 1998;  395 535-547
  PubMedGoogle Scholar
• 6 Baskin D G, Breininger J F, Schwartz M W. Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus.  Diabetes . 1999;  48 828-833
  PubMedGoogle Scholar
• 7 Cheung C C, Clifton D K, Steiner R A. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus.  Endocrinology . 1997;  138 4489-4492
  CrossrefPubMedGoogle Scholar
• 8 Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim M H, Skoda R C. Defective STAT signaling by the leptin receptor in diabetic mice.  Proc Natl Acad Sci U S A . 1996;  93 6231-6235
  CrossrefPubMedGoogle Scholar
• 9 Farooqi I S, Keogh J M, Kamath S. Partial leptin deficiency and human adiposity.  Nature . 2001;  414 34-35
  CrossrefPubMedGoogle Scholar
• 10 Farooqi I S, O'Rahilly S. Recent advances in the genetics of severe childhood obesity.  Arch Dis Child . 2000;  83 31-34
  CrossrefPubMedGoogle Scholar
• 11 Farooqi I S, Jebb S A, Langmack G. Effects of recombinant leptin therapy in a child with congenital leptin deficiency.  N Engl J Med . 1999;  341 879-884
  CrossrefPubMedGoogle Scholar
• 12 Chehab F F, Lim M E, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin.  Nat Genet . 1996;  12 318-320
  CrossrefPubMedGoogle Scholar
• 13 Sinha Y N, Salocks C B, Vanderlaan W P. Prolactin and growth hormone secretion in chemically induced and genetically obese mice.  Endocrinology . 1975;  97 1386-1393
  PubMedGoogle Scholar
• 14 Lord G, Matarese G, Howard J K, Baker R J, Bloom S R, Lechler R I. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.  Nature . 1998;  394 897-901
  CrossrefPubMedGoogle Scholar
• 15 Ahima R S, Prabakaran D, Mantzoros C. Role of leptin in the neuroendocrine response to fasting.  Nature . 1996;  382 250-252
  CrossrefPubMedGoogle Scholar
• 16 Ludwig D S, Mountjoy K G, Tatro J B. Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus.  Am J Physiol . 1998;  274 E627-E633
  PubMedGoogle Scholar
• 17 Cowley M A, Pronchuk N, Fan W, Dinulescu D M, Colmers W F, Cone R D. Integration of NPY, AGRP and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat.  Neuron . 2000;  24 155-163
  PubMedGoogle Scholar
• 18 Badger T M, Lynch E A, Fox P H. Effects of fasting on leutinizing hormone dynamics in the male rat.  J Nutr . 1985;  115 788-797
  PubMedGoogle Scholar
• 19 Yu W H, Kimura M, Walczewska A, Karanth S, McCann S M. Role of leptin in hypothalamic-pituitary function.  Proc Natl Acad Sci U S A . 1997;  94 1023-1028
  CrossrefPubMedGoogle Scholar
• 20 Kalra S P, Dube M G, Pu S, Xu B, Horvath T L, Kalra P S. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.  Endocr Rev . 1999;  20 68-100
  CrossrefPubMedGoogle Scholar
• 21 Broberger C, Johansen J, Johansson C, Schalling M, Hokfelt T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.  Proc Natl Acad Sci U S A . 1998;  95 15043-15048
  CrossrefPubMedGoogle Scholar
• 22 Kristensen P, Judge M E, Thim L. Hypothalamic CART is a new anorectic peptide regulated by leptin.  Nature . 1998;  393 72-76
  CrossrefPubMedGoogle Scholar
• 23 Schwartz M W, Seeley R J, Woods S C. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus.  Diabetes . 1997;  46 2119-2123
  PubMedGoogle Scholar
• 24 Stanley B G, Leibowitz S F. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior.  Proc Natl Acad Sci U S A . 1985;  82 3940-3943
  PubMedGoogle Scholar
• 25 Stanley B G, Kyrkouli S E, Lampert S, Leibowitz S F. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity.  Peptides . 1986;  7 1189-1192
  CrossrefPubMedGoogle Scholar
• 26 Lambert P D, Phillips P J, Wilding J P, Bloom S R, Herbert J. c-fos expression in the paraventricular nucleus of the hypothalamus following intracerebroventricular infusions of neuropeptide Y.  Brain Res . 1995;  670 59-65
  CrossrefPubMedGoogle Scholar
• 27 Bagnol D, Lu X Y, Kaelin C B. Anatomy of an endogenous antagonist: relationship between agouti-related protein and proopiomelanocortin in brain.  J Neurosci . 1999;  19 RC26
  PubMedGoogle Scholar
• 28 Stanley B G, Anderson K C, Grayson M H, Leibowitz S F. Repeated hypothalamic stimulation with neuropeptide Y increases daily carbohydrate and fat intake and body weight gain in female rats.  Physiol Behav . 1989;  46 173-177
  CrossrefPubMedGoogle Scholar
• 29 Sanacora G, Kershaw M, Finkelstein J A, White J D. Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation.  Endocrinology . 1990;  127 730-737
  PubMedGoogle Scholar
• 30 Nakazato M, Murakami N, Date Y. A role for ghrelin in the central regulation of feeding.  Nature . 2001;  409 194-198
  CrossrefPubMedGoogle Scholar
• 31 Schwartz M W, Baskin D G, Bukowski T R. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.  Diabetes . 1996;  45 531-535
  PubMedGoogle Scholar
• 32 Shibasaki T, Oda T, Imaki T, Ling N, Demura H. Injection of anti-neuropeptide Y gamma-globulin into the hypothalamic paraventricular nucleus decreases food intake in rats.  Brain Res . 1993;  601 313-316
  CrossrefPubMedGoogle Scholar
• 33 Erickson J C, Clegg K E, Palmiter R D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y.  Nature . 1996;  381 415-421
  CrossrefPubMedGoogle Scholar
• 34 Erickson J C, Hollopeter G, Palmiter R D. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y.  Science . 1996;  274 1704-1707
  CrossrefPubMedGoogle Scholar
• 35 Naveilhan P, Hassani H, Canals J M. Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor.  Nat Med . 1999;  5 1188-1193
  PubMedGoogle Scholar
• 36 Billington C J, Briggs J E, Grace M, Levine A S. Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism.  Am J Physiol . 1991;  260 R321-R327
  PubMedGoogle Scholar
• 37 Fekete C, Kelly J, Mihaly E. Neuropeptide Y has a central inhibitory action on the hypothalamic-pituitary-thyroid axis.  Endocrinology . 2001;  142 2606-2613
  CrossrefPubMedGoogle Scholar
• 38 Li C, Chen P, Smith M S. Morphological evidence for direct interaction between arcuate nucleus neuropeptide Y (NPY) neurons and gonadotropin-releasing hormone neurons and the possible involvement of NPY Y1 receptors.  Endocrinology . 1999;  140 5382-5390
  CrossrefPubMedGoogle Scholar
• 39 Sahu A, Phelps C P, White J D, Crowley W R, Kalra S P, Kalra P S. Steroidal regulation of hypothalamic neuropeptide Y release and gene expression.  Endocrinology . 1992;  130 3331-3336
  CrossrefPubMedGoogle Scholar
• 40 Crowley W R, Kalra S P. Neuropeptide Y stimulates the release of luteinizing hormone-releasing hormone from medial basal hypothalamus in vitro: modulation by ovarian hormones.  Neuroendocrinology . 1987;  46 97-103
  PubMedGoogle Scholar
• 41 Kalra S P, Kalra P S, Sahu A, Crowley W R. Gonadal steroids and neurosecretion: facilitatory influence on LHRH and neuropeptide Y.  J Steroid Biochem . 1987;  27 677-682
  CrossrefPubMedGoogle Scholar
• 42 Kaynard A H, Pau K Y, Hess D L, Spies H G. Third-ventricular infusion of neuropeptide Y suppresses luteinizing hormone secretion in ovariectomized rhesus macaques.  Endocrinology . 1990;  127 2437-2444
  PubMedGoogle Scholar
• 43 Kalra S P, Crowley W R. Neuropeptide Y: a novel neuroendocrine peptide in the control of pituitary hormone secretion, and its relation to luteinizing hormone.  Front Neuroendocrinol . 1992;  13 1-46
  PubMedGoogle Scholar
• 44 Kalra P S, Bonavera J J, Kalra S P. Central administration of antisense oligodeoxynucleotides to neuropeptide Y (NPY) mRNA reveals the critical role of newly synthesized NPY in regulation of LHRH release.  Regul Pept . 1995;  59 215-220
  CrossrefPubMedGoogle Scholar
• 45 Kalra P S, Dube M G, Kalra S P. Effects of centrally administered antisense oligodeoxynucleotides on feeding behavior and hormone secretion.  Methods Enzymol . 2000;  314 184-200
  PubMedGoogle Scholar
• 46 McDonald J K, Lumpkin M D, Samson W K, McCann S M. Neuropeptide Y affects secretion of luteinizing hormone and growth hormone in ovariectomized rats.  Proc Natl Acad Sci U S A . 1985;  82 561-564
  PubMedGoogle Scholar
• 47 Schulz R, Wilhelm A, Pirke K M, Gramsch C, Herz A. Beta-endorphin and dynorphin control serum luteinizing hormone level in immature female rats.  Nature . 1981;  294 757-759
  CrossrefPubMedGoogle Scholar
• 48 Kalra S P, Allen L G, Sahu A, Kalra P S, Crowley W R. Gonadal steroids and neuropeptide Y-opioid-LHRH axis: interactions and diversities.  J Steroid Biochem . 1988;  30 185-193
  CrossrefPubMedGoogle Scholar
• 49 Simonian S X, Spratt D P, Herbison A E. Identification and characterization of estrogen receptor alpha-containing neurons projecting to the vicinity of the gonadotropin-releasing hormone perikarya in the rostral preoptic area of the rat.  J Comp Neurol . 1999;  411 346-358
  PubMedGoogle Scholar
• 50 Faletti A G, Mastronardi C A, Lomniczi A. beta-Endorphin blocks luteinizing hormone-releasing hormone release by inhibiting the nitricoxidergic pathway controlling its release.  Proc Natl Acad Sci U S A . 1999;  96 1722-1726
  CrossrefPubMedGoogle Scholar
• 51 Walsh J P, Clarke I J. Effects of central administration of highly selective opioid mu-, delta- and kappa-receptor agonists on plasma luteinizing hormone (LH), prolactin, and the estrogen-induced LH surge in ovariectomized ewes.  Endocrinology . 1996;  137 3640-3648
  CrossrefPubMedGoogle Scholar
• 52 Scimonelli T, Celis M E. Modifications in alpha-MSH concentrations in different hypothalamic areas during the estrous cycle in the rat.  Acta Physiol Pharmacol Latinoam . 1986;  36 431-437
  PubMedGoogle Scholar
• 53 Bohler Jr C H, Tracer H, Merriam G R, Petersen S L. Changes in proopiomelanocortin messenger ribonucleic acid levels in the rostral periarcuate region of the female rat during the estrous cycle.  Endocrinology . 1991;  128 1265-1269
  PubMedGoogle Scholar
• 54 Gosnell B A, Levine A S, Morley J E. The stimulation of food intake by selective agonists of mu, kappa and delta opioid receptors.  Life Sci . 1986;  38 1081-1088
  CrossrefPubMedGoogle Scholar
• 55 McLean S, Hoebel B G. Feeding induced by opiates injected into the paraventricular hypothalamus.  Peptides . 1983;  4 287-292
  CrossrefPubMedGoogle Scholar
• 56 Simone D A, Bodnar R J, Goldman E J, Pasternak G W. Involvement of opioid receptor subtypes in rat feeding behavior.  Life Sci . 1985;  36 829-833
  CrossrefPubMedGoogle Scholar
• 57 Arjune D, Bodnar R J. Suppression of nocturnal, palatable and glucoprivic intake in rats by the kappa opioid antagonist, nor-binaltorphamine.  Brain Res . 1990;  534 313-316
  CrossrefPubMedGoogle Scholar
• 58 Horvath T L, Naftolin F, Leranth C. Beta-endorphin innervation of dopamine neurons in the rat hypothalamus: a light and electron microscopic double immunostaining study.  Endocrinology . 1992;  131 1547-1555
  CrossrefPubMedGoogle Scholar
• 59 Kalra P S, Norlin M, Kalra S P. Neuropeptide Y stimulates beta-endorphin release in the basal hypothalamus: role of gonadal steroids.  Brain Res . 1995;  705 353-356
  CrossrefPubMedGoogle Scholar
• 60 Garcia M M, Brown H E, Harlan R E. Alterations in immediate-early gene proteins in the rat forebrain induced by acute morphine injection.  Brain Res . 1995;  692 23-40
  CrossrefPubMedGoogle Scholar
• 61 Xu B, Sahu A, Kalra P S, Crowley W R, Kalra S P. Disinhibition from opioid influence augments hypothalamic neuropeptide Y (NPY) gene expression and pituitary luteinizing hormone release: effects of NPY messenger ribonucleic acid antisense oligodeoxynucleotides.  Endocrinology . 1996;  137 78-84
  CrossrefPubMedGoogle Scholar
• 62 Kandeel F R, Swerdloff R S. The interaction between beta-endorphin and gonadal steroids in regulation of luteinizing hormone (LH) secretion and sex steroid regulation of LH and proopiomelanocortin peptide secretion by individual pituitary cells.  Endocrinology . 1997;  138 649-656
  CrossrefPubMedGoogle Scholar
• 63 Leranth C, Sakamoto H, MacLusky N J, Shanabrough M, Naftolin F. Application of avidin-ferritin and peroxidase as contrasting electron- dense markers for simultaneous electron microscopic immunocytochemical labelling of glutamic acid decarboxylase and tyrosine hydroxylase in the rat arcuate nucleus.  Histochemistry . 1985;  82 165-168
  CrossrefPubMedGoogle Scholar
• 64 Jung H, Shannon E M, Fritschy J M, Ojeda S R. Several GABAA receptor subunits are expressed in LHRH neurons of juvenile female rats.  Brain Res . 1998;  780 218-229
  CrossrefPubMedGoogle Scholar
• 65 McCarthy M M, Kaufman L C, Brooks P J, Pfaff D W, Schwartz-Giblin S. Estrogen modulation of mRNA levels for the two forms of glutamic acid decarboxylase (GAD) in female rat brain.  J Comp Neurol . 1995;  360 685-697
  PubMedGoogle Scholar
• 66 Mitsushima D, Hei D L, Terasawa E. Gamma-aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty.  Proc Natl Acad Sci U S A . 1994;  91 395-399
  PubMedGoogle Scholar
• 67 Gore A C, Roberts J L. Regulation of gonadotropin-releasing hormone gene expression in vivo and in vitro.  Front Neuroendocrinol . 1997;  18 209-245
  PubMedGoogle Scholar
• 68 Mitsushima D, Marzban F, Luchansky L L. Role of glutamic acid decarboxylase in the prepubertal inhibition of the luteinizing hormone releasing hormone release in female rhesus monkeys.  J Neurosci . 1996;  16 2563-2573
  PubMedGoogle Scholar
• 69 Turton M D, O'Shea D, Gunn I. A role for glucagon-like peptide-1 in the central regulation of feeding.  Nature . 1996;  379 69-72
  CrossrefPubMedGoogle Scholar
• 70 Tang-Christensen M, Larsen P J, Thulesen J, Romer J, Vrang N. The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake.  Nat Med . 2000;  6 802-807
  CrossrefPubMedGoogle Scholar
• 71 Dakin C L, Gunn I, Small C J. Oxyntomodulin inhibits food intake in the rat.  Endocrinology . 2001;  142 4244-4250
  CrossrefPubMedGoogle Scholar
• 72 Scrocchi L A, Brown T J, MacLusky N J. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.  Nat Med . 1996;  2 1254-1258
  CrossrefPubMedGoogle Scholar
• 73 Beak S A, Heath M M, Small C J. Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line.  J Clin Invest . 1998;  101 1334-1341
  PubMedGoogle Scholar
• 74 MacLusky N J, Cook S, Scrocchi L. Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling.  Endocrinology . 2000;  141 752-762
  CrossrefPubMedGoogle Scholar
• 75 Boston B A, Blaydon K M, Varnerin J, Cone R D. Independent and additive effects of central POMC and leptin pathways on murine obesity.  Science . 1997;  278 1641-1644
  CrossrefPubMedGoogle Scholar
• 76 Barsh G. From Agouti to Pomc: 100 years of fat blonde mice.  Nat Med . 1999;  5 984-985
  CrossrefPubMedGoogle Scholar
• 77 Cone R D. The central melanocortin system and its role in energy homeostasis.  Ann Endocrinol (Paris) . 1999;  60 3-9
  PubMedGoogle Scholar
• 78 Rossi M, Kim M S, Morgan D G. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo.  Endocrinology . 1998;  139 4428-4431
  CrossrefPubMedGoogle Scholar
• 79 Quillan J M, Sadee W, Wei E T, Jimenez C, Ji L, Chang J K. A synthetic human Agouti-related protein-(83-132)-NH2 fragment is a potent inhibitor of melanocortin receptor function.  FEBS Lett . 1998;  428 59-62
  CrossrefPubMedGoogle Scholar
• 80 Fan W, Boston B A, Kesterson R A, Hruby V J, Cone R D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.  Nature . 1997;  385 165-168
  CrossrefPubMedGoogle Scholar
• 81 Small C J, Kim M S, Stanley S A. Effects of chronic central nervous system administration of agouti-related protein in pair-fed animals.  Diabetes . 2001;  50 248-254
  PubMedGoogle Scholar
• 82 Huszar D, Lynch C A, Fairchild-Huntress V. Targeted disruption of the melanocortin-4 receptor results in obesity in mice.  Cell . 1997;  88 131-141
  CrossrefPubMedGoogle Scholar
• 83 Graham M, Shutter J R, Sarmiento U, Sarosi I, Stark K L. Overexpression of Agrt leads to obesity in transgenic mice.  Nat Genet . 1997;  17 273-274
  PubMedGoogle Scholar
• 84 Yaswen L, Diehl N, Brennan M B, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin [see comments].  Nat Med . 1999;  5 1066-1070
  CrossrefPubMedGoogle Scholar
• 85 Ste-Marie L, Miura G I, Marsh D J, Yagaloff K, Palmiter R D. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.  Proc Natl Acad Sci U S A . 2000;  97 12339-12344
  CrossrefPubMedGoogle Scholar
• 86 Butler A A, Kesterson R A, Khong K. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse.  Endocrinology . 2000;  141 3518-3521
  CrossrefPubMedGoogle Scholar
• 87 Kim M S, Small C J, Stanley S A. The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin.  J Clin Invest . 2000;  105 1005-1011
  PubMedGoogle Scholar
• 88 Forbes S, Bui S, Robinson B R, Hochgeschwender U, Brennan M B. Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway.  Proc Natl Acad Sci U S A . 2001;  98 4233-4237
  CrossrefPubMedGoogle Scholar
• 89 Blake N G, Eckland D J, Foster O J, Lightman S L. Inhibition of hypothalamic thyrotropin-releasing hormone messenger ribonucleic acid during food deprivation.  Endocrinology . 1991;  129 2714-2718
  PubMedGoogle Scholar
• 90 Jackson R S, O'Rahilly S, Brain C, Nussey S S. Proopiomelanocortin products and human early-onset obesity.  J Clin Endocrinol Metab . 1999;  84 819-820
  CrossrefPubMedGoogle Scholar
• 91 Yeo G S, Farooqi I S, Challis B G, Jackson I J, O'Rahilly S. The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models.  Q J Med . 2000;  93 7-14
  PubMedGoogle Scholar
• 92 Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.  J Clin Invest . 2000;  106 253-262
  CrossrefPubMedGoogle Scholar
• 93 Vink T, Hinney A, van Elburg A A. Association between an agouti-related protein gene polymorphism and anorexia nervosa.  Mol Psychiatry . 2001;  6 325-328
  CrossrefPubMedGoogle Scholar
• 94 Fehm H L, Smolnik R, Kern W, McGregor G P, Bickel U, Born J. The melanocortin melanocyte-stimulating hormone/adrenocorticotropin(4-10) decreases body fat in humans.  J Clin Endocrinol Metab . 2001;  86 1144-1148
  CrossrefPubMedGoogle Scholar
• 95 Mountjoy K G, Mortrud M T, Low M J, Simerly R B, Cone R D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.  Mol Endocrinol . 1994;  8 1298-1308
  CrossrefPubMedGoogle Scholar
• 96 Williams G, Cardoso H M, Lee Y C. Hypothalamic regulatory peptides in obese and lean Zucker rats.  Clin Sci (Lond) . 1991;  80 419-426
  PubMedGoogle Scholar
• 97 Mezey E, Kiss J Z, Mueller G P, Eskay R, O'Donohue H L, Palkovits M. Distribution of the pro-opiomelanocortin derived peptides, adrenocorticotrope hormone, alpha-melanocyte-stimulating hormone and beta-endorphin (ACTH, alpha-MSH, beta-END) in the rat hypothalamus.  Brain Res . 1985;  328 341-347
  CrossrefPubMedGoogle Scholar
• 98 Stanley S A, Small C J, Kim M S. Agouti related peptide (Agrp) stimulates the hypothalamo pituitary gonadal axis in vivo & in vitro in male rats.  Endocrinology . 1999;  140 5459-5462
  CrossrefPubMedGoogle Scholar
• 99 Watanobe H, Suda T, Wikberg J E, Schioth H B. Evidence that physiological levels of circulating leptin exert a stimulatory effect on luteinizing hormone and prolactin surges in rats.  Biochem Biophys Res Commun . 1999;  263 162-165
  CrossrefPubMedGoogle Scholar
• 100 Limone P, Calvelli P, Altare F, Ajmone-Catt P, Lima T, Molinatti G M. Evidence for an interaction between alpha-MSH and opioids in the regulation of gonadotropin secretion in man.  J Endocrinol Invest . 1997;  20 207-210
  PubMedGoogle Scholar
• 101 Granholm N H, Jeppesen K W, Japs R A. Progressive infertility in female lethal yellow mice (Ay/a; strain C57BL/6J).  J Reprod Fertil . 1986;  76 279-287
  PubMedGoogle Scholar
• 102 Lambert P D, Couceyro P R, McGirr K M, Dall Vechia E S, Smith Y, Kuhar M J. CART peptides in the central control of feeding and interactions with neuropeptide Y.  Synapse . 1998;  29 293-298
  CrossrefPubMedGoogle Scholar
• 103 Stanley S A, Small C J, Murphy K G. Actions of cocaine- and amphetamine-regulated transcript (CART) peptide on regulation of appetite and hypothalamo-pituitary axes in vitro and in vivo in male rats.  Brain Res . 2001;  893 186-194
  CrossrefPubMedGoogle Scholar
• 104 Abbott C R, Rossi M, Wren A M. Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei.  Endocrinology . 2001;  142 3457-3463
  CrossrefPubMedGoogle Scholar
• 105 Koylu E O, Couceyro P R, Lambert P D, Ling N C, DeSouza E B, Kuhar M J. Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland.  J Neuroendocrinol . 1997;  9 823-833
  CrossrefPubMedGoogle Scholar
• 106 Kojima M, Hosoda H, Matsuo H, Kangawa K. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor.  Trends Endocrinol Metab . 2001;  12 118-122
  PubMedGoogle Scholar
• 107 Tschop M, Smiley D L, Heiman M L. Ghrelin induces adiposity in rodents.  Nature . 2000;  407 908-913
  CrossrefPubMedGoogle Scholar
• 108 Wren A M, Small C J, Ward H L. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.  Endocrinology . 2000;  141 4325-4328
  CrossrefPubMedGoogle Scholar
• 109 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.  Nature . 1999;  402 656-660
  CrossrefPubMedGoogle Scholar
• 110 Wren A M, Seal L J, Cohen M A. Ghrelin enhances appetite and increases food intake in humans.  J Clin Endocrinol Metab . 2001;  86 5992
  CrossrefPubMedGoogle Scholar
• 111 Cummings D E, Purnell J Q, Frayo R S, Schmidova K, Wisse B E, Weigle D S. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans.  Diabetes . 2001;  50 1714-1719
  CrossrefPubMedGoogle Scholar
• 112 Wren A M, Small C J, Abbott C R. Ghrelin causes hyperphagia and obesity in rats.  Diabetes . 2001;  50 2540-2547
  CrossrefPubMedGoogle Scholar
• 113 Tschop M, Weyer C, Tataranni P A, Devanarayan V, Ravussin E, Heiman M L. Circulating ghrelin levels are decreased in human obesity.  Diabetes . 2001;  50 707-709
  CrossrefPubMedGoogle Scholar
• 114 Ravussin E, Tschop M, Morales S, Bouchard C, Heiman M L. Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins.  J Clin Endocrinol Metab . 2001;  86 4547-4551
  CrossrefPubMedGoogle Scholar
• 115 Ariyasu H, Takaya K, Tagami T. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans.  J Clin Endocrinol Metab . 2001;  86 4753-4758
  CrossrefPubMedGoogle Scholar
• 116 Kaji H, Tai S, Okimura Y. Cloning and characterization of the 5′-flanking region of the human growth hormone secretagogue receptor gene.  J Biol Chem . 1998;  273 33885-33888
  CrossrefPubMedGoogle Scholar
• 117 Asakawa A, Inui A, Kaga T. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.  Gastroenterology . 2001;  120 337-345
  CrossrefPubMedGoogle Scholar
• 118 Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression.  Endocrinology . 2000;  141 4797-4800
  CrossrefPubMedGoogle Scholar