TRB3 Regulates Beige Fat Formation in Response to Exercise and Beta-adrenergic Receptor Agonist

Brown adipose tissue (BAT) and a recently identified brown-like adipocyte, beige fat, have been implicated as anti-obese and anti-diabetic tissues due to their ability to dissipate energy as heat by the expression of UCP1. Recent studies have demonstrated that BAT found in adult humans is composed of beige fat and that its activity is significantly increased in response to exercise training and β-adrenergic receptor (β-AR) agonist administration. However, the signaling molecules that regulate beige fat activity during exercise and β-AR activation have not yet been elucidated. TRB3 has been shown to regulate differentiation and metabolism in multiple tissues but the role of the protein in beige fat has not been studied. For this study we tested the hypothesis that TRB3 inhibits beige fat formation and activity, and that inhibition of TRB3 improves beige fat function. In order to examine the role of TRB3 on beige fat formation and function, we injected wild type mice with either saline or CL316,243, a β3-AR agonist, at 1 mg/kg daily for 6 days. TRB3 expression was significantly decreased in the inguinal fat from CL316,243 injected mice compared to saline injected mice by 63%, which was associated with increased UCP1 expression by 249%. We also trained wild type mice in the wheel cages for 8 weeks and found that TRB3 expression was significantly decreased in the inguinal fat from trained mice compared to controls by 42%, whereas UCP1 expression was increased by 84%. We next investigated if knockout of TRB3 promotes exercise training- and β3-AR-induced beige fat formation and found that inguinal fat UCP1 expression was further increased in TRB3KO mice compared to controls after 6 days of CL316,243 injection and 8 week exercise training by 215% and 311%, respectively. Consistent with these findings, TRB3KO mice were cold resistant (rectal temperature at 4°C for 2 hrs: 34.3°C ± 0.4 vs. 35.7°C ± 0.1). These data demonstrate that TRB3 regulates exercise- and β3-AR-induced beige fat formation and activity. 1R16GM149457-01A1 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.