scholarly journals Regulation of adipose tissue leptin secretion by alpha-melanocyte-stimulating hormone and agouti-related protein: further evidence of an interaction between leptin and the melanocortin signalling system

2004 ◽  
Vol 32 (1) ◽  
pp. 145-153 ◽  
Author(s):  
N Hoggard ◽  
L Hunter ◽  
JS Duncan ◽  
DV Rayner
Keyword(s):  
Adipose Tissue ◽  
Energy Balance ◽  
Receptor Subtype ◽  
Related Protein ◽  
Melanocortin System ◽  
Rat Adipocytes ◽  
Melanocyte Stimulating Hormone ◽  
Agouti Related Protein ◽  
Stimulating Hormone

The central role of the melanocortin system in the regulation of energy balance has been studied in great detail. However, the functions of circulating melanocortins and the roles of their peripheral receptors remain to be elucidated. There is increasing evidence of a peripheral action of melanocortins in the regulation of leptin production by adipocytes. Here we investigate the interaction of alpha-melanocyte stimulating hormone (alpha-MSH) and agouti-related protein (AgRP) in the regulation of leptin secretion from cultured rat adipocytes and examine the changes in circulating alpha-MSH and AgRP in lean and obese rodents after hormonal and energetic challenge. Leptin secretion (measured by ELISA) and gene expression (by real-time quantitative PCR) of differentiated rat adipocytes cultured in vitro were inhibited by the administration of alpha-MSH (EC50=0.24 nM), and this effect was antagonised by antagonists of the melanocortin receptors MC4R and MC3R (AgRP and SHU9119). The presence of MC4R in rat adipocytes (RT-PCR and restriction digest) supports the involvement of this receptor subtype in this interaction. Leptin administered to ob/ob mice in turn increases the release of alpha-MSH into the circulation, suggesting a possible feedback loop between the site of alpha-MSH release and the release of leptin from the adipose tissue. However, the physiological significance of this putative feedback probably depends upon the underlying state of energy balance, since in the fasting state low plasma alpha-MSH is paralleled by low plasma leptin.

Mutational analysis of melanocortin-4 receptor, agouti-related protein, and α-melanocyte-stimulating hormone genes in severely obese children

2001 ◽  
Vol 139 (2) ◽  
pp. 204-209 ◽  
Author(s):  
Béatrice Dubern ◽  
Karine Clément ◽  
Véronique Pelloux ◽  
Philippe Froguel ◽  
Jean-Philippe Girardet ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Related Protein ◽  
Obese Children ◽  
Melanocyte Stimulating Hormone ◽  
Melanocortin 4 Receptor ◽  
Severely Obese ◽  
Agouti Related Protein ◽  
Stimulating Hormone

scholarly journals Paraventricular Nucleus Administration of Calcitonin Gene-Related Peptide Inhibits Food Intake and Stimulates the Hypothalamo-Pituitary-Adrenal Axis

Endocrinology ◽  
2003 ◽  
Vol 144 (4) ◽  
pp. 1420-1425 ◽  
Author(s):  
Waljit S. Dhillo ◽  
Caroline J. Small ◽  
Preeti H. Jethwa ◽  
Sabina H. Russell ◽  
James V. Gardiner ◽  
...  
Keyword(s):  
Food Intake ◽  
Hpa Axis ◽  
Male Rats ◽  
Mrna Levels ◽  
Related Protein ◽  
Melanocyte Stimulating Hormone ◽  
Calcitonin Gene ◽  
Agouti Related Protein ◽  
Prior Administration

Abstract Calcitonin gene-related protein (CGRP) inhibits food intake and stimulates the hypothalamo-pituitary-adrenal (HPA) axis after intracerebroventricular injection in rats. However, the hypothalamic site and mechanism of action are unknown. We investigated the effects of intraparaventricular nucleus administration (iPVN) of CGRP on food intake and the HPA axis in rats and the effect of CGRP on the release of hypothalamic neuropeptides in vitro. In addition, we investigated the effects of food deprivation on hypothalamic CGRP expression. CGRP dose-dependently reduced food intake in the first hour after iPVN injection in fasted male rats (saline, 5.1 ± 0.8 g; 0.3 nmol CGRP, 1.1 ± 0.5 g; P < 0.001 vs. saline). iPVN injection of CGRP8–37 (a CGRP1 receptor antagonist) alone had no effect on food intake. However, the reduction in food intake by iPVN CGRP was attenuated by prior administration of CGRP8–37 [CGRP8–37 (10 nmol)/CGRP (0.3 nmol), 3.0 ± 0.8 g; P < 0.05 vs. 0.3 nmol CGRP]. CGRP (100 nm) stimulated the release of α-melanocyte stimulating hormone, cocaine- and amphetamine-related transcript, corticotropin-releasing hormone, and arginine vasopressin from hypothalamic explants to 127 ± 19%, 148 ± 10%, 158 ± 17%, and 198 ± 21% of basal levels, respectively (P < 0.05 vs. basal), but did not alter the release of either neuropeptide Y or agouti-related protein. Hypothalamic CGRP mRNA levels in 24-h fasted rats were increased to 130 ± 8% of control levels [CGRP mRNA (arbitrary units), 4.75 ± 0.4; controls, 3.65 ± 0.34; P < 0.05]. Our data suggest that CGRP administered to the PVN inhibits food intake and stimulates the HPA axis.

scholarly journals Peripherally administered [Nle4,d-Phe7]-α-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice

2004 ◽  
Vol 33 (3) ◽  
pp. 693-703 ◽  
Author(s):  
N Hoggard ◽  
D V Rayner ◽  
S L Johnston ◽  
J R Speakman
Keyword(s):  
Energy Balance ◽  
Energy Expenditure ◽  
Metabolic Rate ◽  
Caloric Restriction ◽  
Blood Brain Barrier ◽  
Resting Metabolic Rate ◽  
Melanocortin Receptors ◽  
Related Protein ◽  
Melanocyte Stimulating Hormone ◽  
Agouti Related Protein

The melanocortin system coordinates the maintenance of energy balance via the regulation of both food intake and energy expenditure. Leptin, a key adipogenic hormone involved in the regulation of energy balance is thought to act by stimulating production, in the hypothalamic arcuate nucleus, of α-melanocyte stimulating hormone (αMSH), a potent agonist of MC3/4 melanocortin receptors located in the paraventricular nucleus of the hypothalamus. Additionally leptin inhibits release of agouti-related protein (AgRP), an MC4R antagonist. During periods of caloric restriction, weight loss is not sustained because compensatory mechanisms, such as reduced resting metabolic rate (RMR) are brought into play. Understanding how these compensatory systems operate may provide valuable targets for pharmaceutical therapies to support traditional dieting approaches. As circulating leptin is reduced during caloric restriction, it may mediate some of the observed compensatory responses. In addition to decreases in circulating leptin levels, circulating AgRP is increased during fasting in rodents while αMSH is decreased. As central administration of AgRP depresses metabolism, we hypothesised that the peripheral rise in AgRP might be involved in signalling the depression of RMR during food restriction. We hypothesised that changes in plasma AgRP and αMSH may coordinate the regulation of changes in energy expenditure acting through central MC4 melanocortin receptors via the sympathetic nervous system. We show here that acute peripherally administered AgRP at supra-physiological concentrations in both lean (C57BL/6) and obese leptin-deficient (ob/ob) mice does not depress RMR, possibly because it crosses the blood–brain barrier very slowly compared with other metabolites. However, in vitro AgRP can decrease leptin secretion, by approximately 40%, from adipocytes into culture medium and may via this axis have an effect on energy metabolism during prolonged caloric restriction. In contrast, peripheral [Nle4,d-Phe7]-α MSH produced a large and sustained increase in resting energy expenditure (0.15 ml O2/min; P <0.05) with a similar response in leptin-deficient ob/ob mice (0.27 ml O2/min) indicating that this effect is independent of the status of leptin production in the periphery. In both cases respiratory exchange ratio and the levels of energy expended on spontaneous physical activity were unaffected by the administration of peripheral [Nle4,d-Phe7]-α MSH. In conclusion, αMSH analogues that cross the blood–brain barrier may significantly augment dietary restriction strategies by sustaining elevated RMR.

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