SORCS1 and SORCS3 control energy balance and orexigenic peptide production

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

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    19 Citations (Scopus)

    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.

    Original languageEnglish
    Article numbere44810
    JournalEMBO Reports
    Volume19
    Issue number4
    DOIs
    Publication statusPublished - Apr 2018

    Keywords

    • TrkB
    • VPS10P domain receptors
    • adiposity
    • agouti-related peptide
    • brain-derived neurotrophic factor

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