SORCS1 and SORCS3 control energy balance and orexigenic peptide production

5 years ago

SORCS1 and SORCS3 control energy balance and orexigenic peptide production

Prateep Sanker Beed, Thomas Rathjen, Dietmar Schmitz, Thomas E Willnow, Anna R Malik, Matthew N Poy, Tilman Breiderhoff, Alexander Stumpf, Gunnar Dittmar, Guido Hermey, Aygul Subkhangulova, Oliver Popp

SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin-related kinase B to attenuate signaling by brain-derived neurotrophic factor, a potent regulator of energy homeostasis. Loss of the joint action of SORCS1 and SORCS3 in mutant mice results in excessive production of the orexigenic neuropeptide agouti-related peptide and in a state of chronic energy excess characterized by enhanced food intake, decreased locomotor activity, diminished usage of lipids as metabolic fuel, and increased adiposity, albeit at overall reduced body weight. Our findings highlight a novel concept in regulation of the melanocortin system and the role played by trafficking receptors SORCS1 and SORCS3 in this process. Diabetes-associated sorting receptors SORCS1 and SORCS3 play a role in central control of metabolism. In mice, loss of the proteins increases production of orexigenic agouti-related peptide, possibly via enhancement of neurotrophin signaling in AgRP neurons.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/embr.201744810