Challenging the Adipocyte Color Barrier—TR Activation Elicits White to Beige Transdifferentiation Independent of Beta-Adrenergic Signaling

Induction of beige adipocytes, or brown-like adipocytes, in white adipose tissues (WAT) has become an alluring possibility to combat diabetes and metabolic diseases. Beige adipocytes express abundant UCP1 protein and exert energy dissipating and thermogenic functions similar to brown adipocytes. In this study, we compared the beiging effects of a synthetic thyroid hormone receptor (TR) agonist, GC1, with the beta-adrenergic receptor (β-AR) agonist CL316243, which is generally accepted as the most efficacious beiging agent, and explored mechanistic similarities and distinctions between the two compounds in a variety of in vitro cell models. Here we show that GC1 induces beiging, in cultured adipocytes derived from inguinal WAT, to a much greater extent than CL316243; in addition, TR activation by GC1 is sufficient to induce beiging in a variety of viscerally derived white adipocytes, as well as 3T3-L1 cells, actions which CL316243 is incapable of. Both GC1 and CL316243 increased expression of ATGL and p-HSL, two key lipases known to be necessary for the activation of UCP1-mediated uncoupling and thermogenesis, although GC1 increased these proteins to a higher extent. Enzymes involved in lipid beta-oxidation, such as ACC/p-ACC and LCAD, are also much more markedly enhanced in GC1-treated cells than those treated with CL316243. Interestingly, the loss of all β-ARs, does not affect the ability of TR activation to elicit beiging, demonstrating that TR agonism induces beiging by novel mechanisms that are independent of beta-adrenergic signaling. Thus, select TR agonists appear to be sufficient to elicit beiging in a fashion that appears to be mechanistically distinct from perhaps all other known beiging agents (nearly all of which require β-AR signaling), making them important tools in assessing the therapeutic potential of beige fat activation to treat diabetes and metabolic disease. Disclosure Y. Xia: None. X. Liang: None. M.E. Lee: None. K. Phillips: None.