TRB3 Inhibits Brown Adipocyte Differentiation and Function by Suppressing Insulin Signaling

Abstract

Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT), the activity of which inversely correlates with obesity and type 2 diabetes. Since BAT has been implicated as an anti‐obese and anti‐diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. Our hypotheses were that TRB3 mediates obesity‐ and diabetes‐induced impairments in BAT differentiation and function, and that inhibition of TRB3 improves BAT function. Here, we report that TRB3 expression in BAT of high‐fat fed mice and ob/ob mice was significantly increased by 56% and 110%; and this coincided with 56% and 58% decreases in the expression of BAT specific uncoupling protein 1, UCP1. Overexpression of TRB3 in brown preadipocytes significantly impaired cell differentiation as assessed by Oil‐Red O staining and expression of genes involved in BAT differentiation and function (UCP1: 73%; PRDM16: 32%; PPARγ: 25%). Consistent with these findings, TRB3KO mice exhibited higher UCP1 mRNA (80%) and protein (780%) expression in BAT, and were cold resistance (rectal temperature at 4oC for 2hrs; WT: 34.3oC ± 0.4 vs. 35.7oC ± 0.1). Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin‐stimulated IRS1 Y612 (38%) and Akt S473 (45%) phosphorylation, whereas TRB3KO mice displayed improved IRS1 Y612 (70%) and Akt S473 (135%) phosphorylation. These data demonstrate that TRB3 regulates BAT differentiation and function presumably by insulin signaling regulation.