HOXC10 Maintains White Adipose Tissue Identity and Its Loss Leads to Enhanced Browning of White Adipose Tissues

Abstract

Increased thermogenesis via increased beige fat development enhances energy expenditure and improves glucose homeostasis. However, thermogenic mechanisms regulating beige adipogenesis within white adipose tissue (WAT) are less understood. The homeobox-containing transcription factor, HOXC10, is traditionally thought to regulate musculoskeletal and patterning of limb development in mammals. We found that HOXC10 is expressed in subcutaneous WAT. Ectopic expression of HOXC10 in adipocytes suppressed brown markers genes, while knockdown of HOXC10 upregulates brown genes expression. To investigate the functional role of HOXC10 in adipose tissue, we generated adipose-specific HOXC10 knockout (AHKO) mice using adiponectin-Cre mice. We show that development of functional beige adipocytes within subcutaneous WAT is enhanced in AHKO mice, contributing to decreased white fat in the lean AHKO mice kept at room temperature. Furthermore, AHKO mice show reduced weight gain, lower fat mass and improved glucose tolerance compared to wild type (WT) mice when fed on high fat diet. Interestingly, AHKO mice exhibit enhanced thermogenic response to cold exposure. These mice also show increased energy expenditure, alongside increased in brown fat markers in subcutaneous WAT, with no effect on classical BAT. These data indicate that HOXC10 plays a critical role in maintaining white adipose tissue identity, and loss of HOXC10 promotes browning in WAT. Disclosure A.H.Y. Tan: None. S. Gun: None. W. Han: None.