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Unravelling the mysterious roles of melanocortin-3 receptors in metabolic homeostasis and obesity using mouse genetics

International Journal of Obesity Supplements volume 4, pages S37–S44 (2014)Cite this article

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Abstract

The central nervous melanocortin system maintains body mass and adiposity within a ‘healthy’ range by regulating satiety and metabolic homeostasis. Neural melanocortin-4 receptors (MC4R) modulate satiety signals and regulate autonomic outputs governing glucose and lipid metabolism in the periphery. The functions of melanocortin-3 receptors (MC3R) have been less well defined. We have observed that food anticipatory activity (FAA) is attenuated in Mc3r−/− mice housed in light:dark or constant dark conditions. Mc3r−/− mice subjected to the restricted feeding protocol that was used to induce FAA also developed insulin resistance, dyslipidaemia, impaired glucose tolerance and evidence of a cellular stress response in the liver. MC3Rs may thus function as modulators of oscillator systems that govern circadian rhythms, integrating signals from nutrient sensors to facilitate synchronizing peak foraging behaviour and metabolic efficiency with nutrient availability. To dissect the functions of MC3Rs expressed in hypothalamic and extra-hypothalamic structures, we inserted a ‘lox-stop-lox’ (TB) sequence into the Mc3r gene. Mc3rTB/TB mice recapitulate the phenotype reported for Mc3r−/− mice: increased adiposity, accelerated diet-induced obesity and attenuated FAA. The ventromedial hypothalamus exhibits high levels of Mc3r expression; however, restoring the expression of the LoxTB Mc3r allele in this nucleus did not restore FAA. However, a surprising outcome came from studies using Nestin-Cre to restore the expression of the LoxTB Mc3r allele in the nervous system. These data suggest that ‘non-neural’ MC3Rs have a role in the defence of body weight. Future studies examining the homeostatic functions of MC3Rs should therefore consider actions outside the central nervous system.

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Acknowledgements

The research described in this article has been supported by the NIDDK (DK0730189) and TSRI-Florida.

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  1. Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA

    C Girardet, K Begriche & A A Butler

  2. The Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA

    A Ptitsyn & R A Koza

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RAK has received grant support from Zafgen. AAB has received grant support through a Novo Nordisk Diabetes Innovation Award. The remaining authors declare no conflict of interest.

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This article is published as part of a supplement sponsored by the Université Laval's Research Chair in Obesity in an effort to inform the public on the causes, consequences, treatments, and prevention of obesity.

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Girardet, C., Begriche, K., Ptitsyn, A. et al. Unravelling the mysterious roles of melanocortin-3 receptors in metabolic homeostasis and obesity using mouse genetics. Int J Obes Supp 4 (Suppl 1), S37–S44 (2014). https://doi.org/10.1038/ijosup.2014.10

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