posted on 2021-05-14, 14:17authored byH. 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.
This study was funded by the Agency of Science, Technology and Research (A*STAR), Singapore.