TRIM56 Promotes White Adipose Tissue Browning to Attenuate Obesity by Degrading TLE3

Abstract In mammals, the activation of thermogenic adipocytes, such as beige and brown adipocytes, can significantly increase overall energy expenditure, offering a promising strategy to combat metabolic diseases. Despite its considerable potential, the regulatory mechanisms governing this activation remain largely elusive. This study bridges this gap by elucidating that tripartite motif 56 (TRIM56), an E3 ubiquitin ligase, is upregulated in response to cold stimuli, thereby promoting the recruitment of beige adipocytes. Notably, the overexpression of TRIM56 in adipocytes is shown to help mice maintain a core temperature under cold conditions, as well as confer protection against diet‐induced obesity. Mechanistically, TRIM56 facilitates the degradation of the transducin‐like enhancer protein 3 (TLE3) protein by promoting its K48‐linked ubiquitination, which subsequently triggers the activation of thermogenic genes in subcutaneousl white adipose tissue and improved the metabolic profiles. These findings unveil a novel function for TRIM56 in adipocyte browning, suggesting its potential as a therapeutic target for the treatment of metabolic disorders.