Melanocortin Type 3 Receptors May Have Central and Peripheral Effects on Body Composition and Food Intake

The melanocortin system is one of the key systems involved in the regulation of ingestive behaviour. Thus, for example, genetic variants of the melanocortin type 4 receptor (Mc4R), have been found to be among the most common mutations associated with severe obesity (in about 5% of cases).

Other studies have also suggested a role for the Mc3R in the regulation of weight gain and food intake, especially with regard to its relationship to circadian rhythms. This is perhaps not surprising, given that the ventromedial hypothalamus (VMH), a critical node in the neural networks regulating feeding-related behaviors and metabolic homeostasis, exhibits dense Mc3R expression relative to other brain regions. In addition, Mc3R is also expressed in the limbic system as well as in peripheral tissues.

A study by Karima Bergriche and colleagues from the Scripps Research Institute, just published in the Journal of Biological Chemistry, shows that the Mc3R may affect body fat and food intake through both central and peripheral mechanisms.

Using a combination of Mc3R knockout mice with neural specific Mc3R expression, the investigators were able to dissect the role of these receptors and brain regions in food intake and metabolism.

Thus, although the knockout animals displayed reduced lean mass, increased fat mass, and accelerated diet-induced obesity (DIO), the attempt to rescue these mice by Mc3R expression in their nervous systems only partially rescued obesity in chow-fed conditions, and had no impact on the accelerated DIO phenotype.

More specifically targeting Mc3R expression to the VMH, despite marked improvements in metabolism also had little impact on obesity.

The authors interpret this findings to indicate that MC3Rs affect energy homeostasis through both central (neuronal) and peripheral mechanisms and that the effects of these receptors on behavior and metabolism involve divergent pathways.

Or, as the authors put it:

“Our data suggests that actions of MC3R in these neurones significantly impacts on metabolic homeostasis, but is not sufficient restore body composition to normal or for regulating expression of complex behaviours associated with food anticipation.”

Clearly, better understanding the pathways and mechanisms involved in these effects may lead to drugs that can perhaps help target this system to improve metabolism and treat obesity.

As always, what works in animals, does not necessarily directly lead to effective and safe medications for humans. Nevertheless, identifying drugable targets is certainly the first first step towards hopefully finding better treatments for obesity and related metabolic problems.

Edmonton, Alberta

Begriche K, Levasseur PR, Zhang J, Rossi J, Skorupa D, Solt LA, Young B, Burris TP, Marks DL, Mynatt RL, & Butler AA (2011). Genetic dissection of melanocortin-3 receptor function suggests roles for central and peripheral receptors in energy homeostasis. The Journal of biological chemistry PMID: 21984834