Peripherally administered [Nle(4),D-Phe(7)]-alpha-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice

N Hoggard, D V Rayner, S L Johnston, J R Speakman

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 alpha-melanocyte stimulating hormone (alphaMSH), 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 alphaMSH 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 aMSH 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 [NIe(4),D-Phe(7)]-alphaMSH produced a large and sustained increase in resting energy expenditure (0.15 ml O-2/min; P<0.05) with a similar response in leptin-deficient ob/ob mice (0.27 ml O-2/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 [Nle(4),D-Phe(7)]-alphaMSH. In conclusion, alphaMSH analogues that cross the blood-brain barrier may significantly augment dietary restriction strategies by sustaining elevated RMR.

Original languageEnglish
Pages (from-to)693-703
Number of pages11
JournalJournal of Molecular Endocrinology
Volume33
DOIs
Publication statusPublished - 2004

Keywords

  • MELANOCORTIN SYSTEM
  • OXYGEN-CONSUMPTION
  • GENE-EXPRESSION
  • ADIPOSE-TISSUE
  • ENERGY-BALANCE
  • WEIGHT-LOSS
  • OBESE GENE
  • ALPHA-MSH
  • LEPTIN
  • EXPENDITURE

Cite this

@article{0c225225a02348dfa9736578cf73daa2,
title = "Peripherally administered [Nle(4),D-Phe(7)]-alpha-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice",
abstract = "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 alpha-melanocyte stimulating hormone (alphaMSH), 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 alphaMSH 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 aMSH 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 [NIe(4),D-Phe(7)]-alphaMSH produced a large and sustained increase in resting energy expenditure (0.15 ml O-2/min; P<0.05) with a similar response in leptin-deficient ob/ob mice (0.27 ml O-2/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 [Nle(4),D-Phe(7)]-alphaMSH. In conclusion, alphaMSH analogues that cross the blood-brain barrier may significantly augment dietary restriction strategies by sustaining elevated RMR.",
keywords = "MELANOCORTIN SYSTEM, OXYGEN-CONSUMPTION, GENE-EXPRESSION, ADIPOSE-TISSUE, ENERGY-BALANCE, WEIGHT-LOSS, OBESE GENE, ALPHA-MSH, LEPTIN, EXPENDITURE",
author = "N Hoggard and Rayner, {D V} and Johnston, {S L} and Speakman, {J R}",
year = "2004",
doi = "10.1677/jme.1.01632",
language = "English",
volume = "33",
pages = "693--703",
journal = "Journal of Molecular Endocrinology",
issn = "0952-5041",
publisher = "Society for Endocrinology",

}

TY - JOUR

T1 - Peripherally administered [Nle(4),D-Phe(7)]-alpha-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice

AU - Hoggard, N

AU - Rayner, D V

AU - Johnston, S L

AU - Speakman, J R

PY - 2004

Y1 - 2004

N2 - 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 alpha-melanocyte stimulating hormone (alphaMSH), 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 alphaMSH 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 aMSH 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 [NIe(4),D-Phe(7)]-alphaMSH produced a large and sustained increase in resting energy expenditure (0.15 ml O-2/min; P<0.05) with a similar response in leptin-deficient ob/ob mice (0.27 ml O-2/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 [Nle(4),D-Phe(7)]-alphaMSH. In conclusion, alphaMSH analogues that cross the blood-brain barrier may significantly augment dietary restriction strategies by sustaining elevated RMR.

AB - 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 alpha-melanocyte stimulating hormone (alphaMSH), 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 alphaMSH 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 aMSH 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 [NIe(4),D-Phe(7)]-alphaMSH produced a large and sustained increase in resting energy expenditure (0.15 ml O-2/min; P<0.05) with a similar response in leptin-deficient ob/ob mice (0.27 ml O-2/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 [Nle(4),D-Phe(7)]-alphaMSH. In conclusion, alphaMSH analogues that cross the blood-brain barrier may significantly augment dietary restriction strategies by sustaining elevated RMR.

KW - MELANOCORTIN SYSTEM

KW - OXYGEN-CONSUMPTION

KW - GENE-EXPRESSION

KW - ADIPOSE-TISSUE

KW - ENERGY-BALANCE

KW - WEIGHT-LOSS

KW - OBESE GENE

KW - ALPHA-MSH

KW - LEPTIN

KW - EXPENDITURE

U2 - 10.1677/jme.1.01632

DO - 10.1677/jme.1.01632

M3 - Article

VL - 33

SP - 693

EP - 703

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

SN - 0952-5041

ER -