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HOXC10 suppresses browning to maintain white adipocyte identity

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posted on 14.05.2021, 14:17 by H. Y. Angeline Tan, M. F. Michelle Sim, Shi-Xiong Tan, Yvonne Ng, Sin Yee Gan, Hongyu Li, Suat Peng Neo, Jayantha Gunaratne, Feng Xu, Weiping Han
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 tolerance and improved glucose homeostasis. These phenotypes were further exacerbated by exposure to cold or a β-adrenergic stimulant. Mechanistically, cold and β-adrenergic exposure led to reduced HOXC10 protein level without affecting its mRNA level. Cold exposure induced PKA-dependent proteasome-mediated degradation of HOXC10 in cultured adipocytes and shotgun proteomics approach identified KCTD 2, 5 and 17 as potential E3 ligases regulating HOXC10 proteasomal degradation. Collectively, these data demonstrate that HOXC10 is a gatekeeper of WAT identity, and targeting HOXC10 could be a plausible therapeutic strategy to unlock WAT thermogenic potentials.

Funding

This study was funded by the Agency of Science, Technology and Research (A*STAR), Singapore.

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