A novel CLK1‐THRAP3‐PPARγ axis is involved in the regulation of insulin sensitivity

Increasing energy expenditure by promoting “browning” in adipose tissues is a promising strategy to prevent obesity and associated diabetes. To explore potential targets of cold exposure, which induces energy expenditure, we performed phosphoproteomics profiling in brown adipose tissue of mice that were housed in mild cold exposure at 16°C. We identified that CLK1 (CDC2‐like kinase 1) is one of the kinases that were significantly downregulated by mild cold exposure. In addition, chemical inhibition or genetic knockout of CLK1 in mice prevented diet‐induced obesity and insulin resistance at 22°C. By proteomics approach, we uncovered a protein, THRAP3 (thyroid hormone receptor‐associated protein 3), as an interacting partner of CLK1, which was confirmed by co‐immunoprecipitation assays. We further identified that CLK1 phosphorylated THRAP3 at Ser243, required for interaction with phosphorylated PPARγ (peroxisome proliferator activated receptor gamma), resulting in downregulation of adipsin expression in adipose tissue and insulin sensitivity. These data suggest that CLK1 plays a critical role in controlling energy expenditure through the CLK1‐Thrap3‐PPARγ axis. Support or Funding Information The studies were supported by NIH grants HL122664 (to L. Chang), HL068878 (to Y.E. Chen)