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Blockage of PPARg T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions

ABSTRACT: Beige adipocytes in mammalian white adipose tissue (WAT) can reinforce fat catabolism and energy expenditure. Promoting beige adipocyte biogenesis is a tantalizing tactic for combating obesity and its associated metabolic disorders. Here, we report that a previously unidentified phosphorylation pattern (Thr166) in the DNA-binding domain of PPARg regulates the inducibility of beige adipocytes. This unique posttranslational modification (PTM) pattern influences allosteric communication between PPARg and DNA or coactivators, which impedes the PPARg-mediated transactivation of beige cell-related gene expression in WAT. The genetic mutation mimicking T166 phosphorylation (p-T166) hinders the inducibility of beige adipocytes. In contrast, genetic or chemical intervention in this PTM pattern favors beige cell formation. Moreover, inhibition of p-T166 attenuates metabolic dysfunction in obese mice. Our results uncover a mechanism involved in beige cell fate determination. Moreover, our discoveries provide a promising strategy for guiding the development of novel PPARg agonists for the treatment of obesity and related metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE158615 | GEO | 2022/10/28

REPOSITORIES: GEO

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