Tbx15 is required for adipocyte browning induced by adrenergic signaling pathway

Wei Sun, Xuemei Zhao, Zhengqi Wang, Yi Chu, Liufeng Mao, Shaoqiang Lin, Xuefei Gao, Yuna Song, Xiaoyan Hui, Shiqi Jia, Shibing Tang, Yong Xu, Aimin Xu, Kerry Loomes, Cunchuan Wang, Donghai Wu, Tao Nie

TBX15 (T-box 15) is a transcription factor that plays an important role in the adipogenesis of primary brown and beige adipocyte precursors. To further elucidate its role in adipose tissues, Sun, Zhao, and colleagues generated adipose-specific Tbx15 knockout mice. They demonstrate that Tbx15 is important for adipocyte thermogenesis and browning in adipose tissue in vivo. Interventions that increase TBX15 expression may provide new therapeutic strategies to promote thermogenesis and combat obesity and related metabolic disorders.

Objective: The T-box gene Tbx15 is abundantly expressed in adipose tissues, especially subcutaneous and brown fat. Although its expression is correlated with obesity, its precise biological role in adipose tissue is poorly understood in vivo. Here we investigated the function of Tbx15 in brown adipose thermogenesis and white adipose browning in vivo.

Methods: In the present study, we generated adipose-specific Tbx15 knockout (AKO) mice by crossing Tbx15 floxed mice with adiponectin-Cre mice to delineate Tbx15 function in adipose tissues. We systematically investigated the influence of Tbx15 on brown adipose thermogenesis and white adipose browning in mice, as well as the possible underlying molecular mechanism.

Results: Upon cold exposure, adipocyte browning in inguinal adipose tissue was significantly impaired in Tbx15 AKO mice. Furthermore, ablation of Tbx15 blocked adipocyte browning induced by β3 adrenergic agonist CL 316243, which did not appear to alter the expression of Tbx15. Analysis of DNA binding sites using chromatin-immunoprecipitation (ChIP) revealed that TBX15 bound directly to a key region in the Prdm16 promoter, indicating it regulates transcription of Prdm16, the master gene for adipocyte thermogenesis and browning. Compared to control mice, Tbx15 AKO mice displayed increased body weight gain and decreased whole body energy expenditure in response to high fat diets.

Conclusions: Taken together, these findings suggest that Tbx15 regulates adipocyte browning and might be a potential target for the treatment of obesity.