SORCS1 and SORCS3 control energy balance and orexigenic peptide production.

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

doi:10.15252/embr.201744810

Abstract

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.

Highlights

VPS10P domain receptors are a unique class of sorting receptors that direct the intracellular transport of target proteins between Golgi, cell surface, and endosomes in mammalian cell types
SORCS1 and SORCS3 in central control of metabolism Aygul Subkhangulova et al Because surface exposure and activity of tropomyosin-related kinase B (TrkB), the receptor for brain-derived neurotrophic factor (BDNF) is decreased in SORCS1/3-deficient neurons, we propose that aberrant TrkB signaling in hypothalamic neurons causes a chronic increase in agoutirelated peptide (AgRP) expression, which, in turn, results in the elevated food intake and defective nutrient partitioning seen in the mutant mice
Though the mutant mice showed a mild impairment in glucose tolerance at young age (12 weeks; Fig EV2B and C), this phenotype did not progress to hyperglycemia during aging (Fig EV3A), suggesting that SORCS1 and SORCS3 are dispensable for glycemic control in chow-fed mice

Summary

Introduction

VPS10P domain receptors are a unique class of sorting receptors that direct the intracellular transport of target proteins between Golgi, cell surface, and endosomes in mammalian cell types. Earlier work has largely focused on a role of VPS10P domain receptors in control of protein transport in neurons, and its relevance for functional integrity and diseases of the brain, including Alzheimer and Huntington disease, frontotemporal lobar dementia, and schizophrenia Genomewide investigations in humans and animal models have associated VPS10P domain receptors with disorders of the systemic metabolism, including hypercholesterolemia [3], diabetes [4,5,6], and obesity [7,8], suggesting involvement of these receptors in control of metabolism that warrants further clarification. Sorting-related receptor CNS expressed (SORCS) 1 exemplifies a member of the VPS10P domain receptor gene family involved in metabolic control [9]. The exact role of SORCS3 in control of metabolism, and its functional interaction with SORCS1, if any, remains unclear

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