A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors

Marie, Linda Ste.; Miura, Grant; Marsh, Donald J.; Yagaloff, Keith A.; Palmiter, Richard D.

doi:10.1073/pnas.220409497

Cited by 334 publications

(242 citation statements)

References 37 publications

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“…The present data give further support to the notion that the MC4 receptor is not only involved in a satiety response but also mediates an important influence on the metabolic status of the animals. A recent study shows that MC4 receptor-null mice have enhanced caloric efficiency (Ste Marie et al 2000), similar to that seen in the agouti obesity syndrome and in MC3 receptor-null mice (Butler et al 2000, Chen et al 2000. It is thus likely that both the MC3 and MC4 receptors are involved in the long-term effects that were observed on the food conversion ratio in this study.…”

Section: Discussionsupporting

confidence: 80%

Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats

Jónsson

Skarphedinsson

Skúladóttir³

et al. 2002

Journal of Endocrinology

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The central melanocortin system is involved in the regulation of food intake and body weight. In this study, we investigated the effect of a 4-week intracerebroventricular infusion of the melanocortin receptor agonist MT-II and the selective melanocortin-4 receptor antagonist HS024 on food intake and body weight homeostasis. The MT-IItreated rats ate less and lost considerably more weight than the control rats during the first week of treatment. During the second and third week, they gained weight and, by the end of the treatment period, the weight gain was similar to that of the control rats. The HS024 treatment caused hyperphagia and development of obesity during the entire period. Extensive accumulations of fat and a sixfold increase in leptin levels were observed in the HS024-treated rats, as compared with controls, after the 4-week period. Food conversion ratio, defined as body weight increase relative to weight of ingested food, was clearly increased in the HS024-treated rats, while it was lowered in the MT-II-treated rats compared with controls. The effect on food conversion ratio was transient, being greatest for both experimental groups during the first week and it was then attenuated to reach the level of controls at the end of the study. The results suggest that long-term injection of exogenous melanocortin receptor active substances may have an important transient effect on food conversion.

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Section: Discussionsupporting

confidence: 80%

Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats

Jónsson

Skarphedinsson

Skúladóttir³

et al. 2002

Journal of Endocrinology

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“…Thus the phenotypic feature of a deficit in energy expenditure that we have previously described in Pomc Ϫ/Ϫ mice (8) appears to be as a result of melanocortin deficiency rather than secondary to glucocorticoid insufficiency. This is in keeping with the phenotype of Mc4R Ϫ/Ϫ mice, another wellcharacterized model of melanocortin dysfunction, which are corticosterone replete but still consume 20% less oxygen then wild-type mice (30).…”

Section: Ap Coll and Associatessupporting

confidence: 76%

Proopiomelanocortin-Deficient Mice Are Hypersensitive to the Adverse Metabolic Effects of Glucocorticoids

et al. 2005

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Congenital lack of proopiomelanocortin (POMC) causes obesity and glucocorticoid deficiency. The responses of PomcϪ/Ϫ and wild-type mice to the administration of corticosterone were compared. In study 1, mice were given corticosterone-supplemented water (CORT) for 10 days, resulting in plasma CORT levels within the physiological range, with partial suppression of hypothalamic corticotropin-releasing hormone expression to a similar degree between genotypes. Body weight, fat mass, and food intake increased in CORT-treated Pomc Ϫ/Ϫ but not wild-type mice. CORT increased plasma insulin levels 50-fold in Pomc Ϫ/Ϫ versus 14-fold in wildtype mice (P < 0.01) and increased hypothalamic agouti-related protein (AgRP) expression by more than 200% in Pomc Ϫ/Ϫ versus 40% in wild type (P < 0.05). In study 2, mice were given CORT from weaning, and Pomc Ϫ/Ϫ but not wild-type mice developed hyperglycemia, ketonuria, and hepatic steatosis by 8 -12 weeks. Thus, Pomc Ϫ/Ϫ mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Additionally, as the levels of plasma CORT achieved, especially in study 1, were not grossly supraphysiological, we conclude that glucocorticoid deficiency may afford Pomc Ϫ/Ϫ mice some protection from the full adverse consequences of melanocortin deficiency. This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state. Diabetes 54:2269 -2276, 2005 P roopiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive, tissue-specific posttranslation modification to generate a range of smaller, biologically active peptides (1). These include ACTH and ␣-, ␤-, and ␥-melanocyte-stimulating hormone, collectively known as the melanocortins. Hypothalamic neurons expressing POMC are critically involved in the integration of nutritional and hormonal signals and the regulation of both appetite and energy expenditure (2). ACTH produced in the anterior pituitary is essential for adrenal steroidogenesis (3), and local production of melanocortins in the skin and hair follicles is critically involved in control of pigmentation (4,5). As expected, inactivating mutations of the POMC gene in humans and mice therefore result in a complex phenotype involving hyperphagia, obesity, glucocorticoid deficiency, and altered pigmentation (6 -9).Among murine models of obesity, Pomc-null mice are unusual in that obesity and hyperphagia develop in the absence of circulating glucocorticoid. Glucocorticoids have pleiotropic effects on metabolism, and in particular, changes in circulating levels of glucocorticoid can impact on the melanocortin system. For example, adrenalectomy is able to reverse the obese phenotype and restore hypothalamic melanocortin tone in leptin-deficient ob/ob mice (10). In addition, adrenalectomy alters the sensitivity of the central melanocortin system to the effects of the melanocortin antagonist agouti-related protein (AgRP), with the orexigenic effect of the latter being absent in adrenalectomized rats but restored with glucocorticoid supplementation (1...

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“…The data suggested that MC4R deficiency may enhance the metabolic efficiency. 14 In a pharmacological study, Adage et al 46 performed a PF study to evaluate the food intake-independent mechanisms of the melanocortin system in the development of obesity. Administration of the melanocortin receptor antagonist SHU9119 to rats reduced spontaneous locomotor activity and body temperature.…”

Section: Discussionmentioning

confidence: 99%

“…14 Ste Marie et al 14 found that the locomotor activity of young male nonobese MC4R knockout mice was significantly lower than that of wild-type mice. When normal mice were switched from a low-fat to a moderate-fat diet, they responded with an increased activity.…”

Section: Introductionmentioning

confidence: 99%

Melanocortin-4 receptor gene and physical activity in the Québec Family Study

et al. 2004

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Physical inactivity is a risk factor for numerous chronic diseases. Low compliance with interventions to increase activity suggests involvement of biological systems. OBJECTIVE: To examine whether sequence variants in genes encoding neuropeptides and receptors in the arcuate and paraventricular nucleus of the hypothalamus contribute to variations in physical activity level in the Québec Family Study. METHODS: We genotyped polymorphisms in the melanocortin-4 receptor (MC4R), melanocortin-3 receptor (MC3R), neuropeptide-Y (NPY), neuropeptide-Y Y1 receptor (NPY Y1R), cocaine-and amphetamine-regulated transcript (CART), agoutirelated protein (AGRP), and pro-opiomelanocortin (POMC) genes in 669 subjects (age (X7s.d.): parents: 5273.4 y; offspring: 2878.7 y). Total physical activity, moderate-to-strenuous activity, and inactivity phenotypes were estimated from a three-day record. The past year's physical activity level was assessed from a questionnaire. Associations between the physical activity phenotypes and the polymorphisms were analyzed using the MIXED model (SAS). RESULTS: The MC4R-C-2745T variant showed significant associations with physical activity phenotypes. The lowest moderateto-strenuous activity scores (P ¼ 0.005) and the highest inactivity scores (P ¼ 0.01) emerged in the T/T genotype. Exclusion of obese subjects increased the association. For inactivity, the association of the MC4R-C-2745T variant was strongest in the offspring (P ¼ 0.002). The T/T offspring had both the highest inactivity score and the lowest body mass index. The CART-A1475G variant modified the associations with MC4R-C-2745T; T/T homozygotes had the lowest activity scores when they also had the A/A CART-A1475G genotype. No significant associations were observed with polymorphisms in the other neuropeptides. CONCLUSION: These findings suggest that DNA sequence variation at the MC4R gene locus may contribute to the propensity to be sedentary.

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A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors

Cited by 334 publications

References 37 publications

Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats

Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats

Proopiomelanocortin-Deficient Mice Are Hypersensitive to the Adverse Metabolic Effects of Glucocorticoids

Melanocortin-4 receptor gene and physical activity in the Québec Family Study

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