Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

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Abstract

<p class="first" id="d9215547e89">Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation. Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling. </p>

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A role for melanin-concentrating hormone in the central regulation of feeding behaviour.

D. Qu, D. S. Ludwig, S Gammeltoft … (1996)

The hypothalamus plays a central role in the integrated regulation of energy homeostasis and body weight, and a number of hypothalamic neuropeptides, such as neuropeptide Y (ref. 1), galanin, CRH (ref. 3) and GLP-1 (ref. 4), have been implicated in the mediation of these effects. To discover new hypothalmic peptides involved in the regulation of body weight, we used differential display polymerase chain reaction to identify messenger RNAs that are differentially expressed in the hypothalamus of ob/+ compared with ob/ob C57B1/6J mice. We show here that one mRNA that is overexpressed in the hypothalamus of ob/ob mice encodes the neuropeptide melanin-concentrating hormone (MCH). Fasting further increased expression of MCH mRNA in both normal and obese animals. Neurons containing MCH are located in the zona incerta and in the lateral hypothalamus. These areas are involved in regulation of ingestive behaviour, but the role of MCH in mammalian physiology is unknown. To determine whether MCH is involved in the regulation of feeding, we injected MCH into the lateral ventricles of rats and found that their food consumption increased. These findings suggest that MCH participates in the hypothalamic regulation of body weight.

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Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.

O Varlamov, Peter R. Carroll, Patsy M. Nishina … (1995)

Mice homozygous for the fat mutation develop obesity and hyperglycaemia that can be suppressed by treatment with exogenous insulin. The fat mutation maps to mouse chromosome 8, very close to the gene for carboxypeptidase E (Cpe), which encodes an enzyme (CPE) that processes prohormone intermediates such as proinsulin. We now demonstrate a defect in proinsulin processing associated with the virtual absence of CPE activity in extracts of fat/fat pancreatic islets and pituitaries. A single Ser202Pro mutation distinguishes the mutant Cpe allele, and abolishes enzymatic activity in vitro. Thus, the fat mutation represents the first demonstration of an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.

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Appetite-suppressing effects of urocortin, a CRF-related neuropeptide.

Ernani Basso, E Merlo, M Spina … (1996)

The neuropeptide corticotropin-releasing factor (CRF) is well known to act on the central nervous system in ways that mimic stress and result in decreases in exploration, increases in sympathetic activity, decreases in parasympathetic outflow, and decreases in appetitive behavior. Urocortin, a neuropeptide related to CRF, binds with high affinity to the CRF2 receptor, is more potent than CRF in suppressing appetite, but is less potent than CRF in producing anxiety-like effects and activation. Doses as low as 10 nanograms injected intracerebroventricularly were effective in decreasing food intake in food-deprived and free-feeding rats. These results suggest that urocortin may be an endogenous CRF-like factor in the brain responsible for the effects of stress on appetite.

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Journal

Title: Science

Abbreviated Title: Science

Publisher: American Association for the Advancement of Science (AAAS)

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date Created: October 03 1997

Publication date (Print): October 03 1997

Publication date (Electronic): October 03 1997

Volume: 278

Issue: 5335

Pages: 135-138

Article

DOI: 10.1126/science.278.5335.135

PubMed ID: 9311920

SO-VID: 272bbc30-14a2-40ca-bc33-47e68f532616

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Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

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Most cited references 4

A role for melanin-concentrating hormone in the central regulation of feeding behaviour.

Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.

Appetite-suppressing effects of urocortin, a CRF-related neuropeptide.

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