HOXC10 Suppresses Browning to Maintain White Adipocyte Identity

Abstract

Promoting beige adipocyte development within white adipose tissue (WAT) is a potential therapeutic approach to staunch the current obesity epidemic. Previously, we identified homeobox-containing transcription factor HOXC10 as a suppressor of browning in subcutaneous WAT. Here, we provide evidence for the physiological role of HOXC10 in regulating WAT thermogenesis. Analysis of an adipose-specific HOXC10 knockout mouse line with no detectable HOXC10 in mature adipocytes revealed spontaneous subcutaneous WAT browning, increased expression of genes involved in browning, increased basal rectal temperature, enhanced cold toler-ance, and improved glucose homeostasis. These pheno-types were further exacerbated by exposure to cold or a b-adrenergic stimulant. Mechanistically, cold and b-adre-nergic exposure led to reduced HOXC10 protein level without affecting its mRNA level. Cold exposure induced cAMP-dependent protein kinase–dependent proteasome-mediated degradation of HOXC10 in cultured adipocytes, and shotgun proteomics approach identified KCTD2, 5, and 17 as potential E3 ligases regulating HOXC10 protea-somal degradation. Collectively, these data demonstrate that HOXC10 is a gatekeeper of WAT identity, and target-ing HOXC10 could be a plausible therapeutic strategy to unlock WAT thermogenic potentials.