1953-P: PPARγ Agonism and FGF-21 Synergize to Robustly Induce Browning of White Fat

Abstract

Increasing brown adipose tissue abundance or activity or converting white into brown adipocytes holds promise for the treatment of type 2 diabetes and obesity. Several PPARγ agonists, including rosiglitazone, have been shown to robustly induce browning of white adipose tissue (WAT) in vitro but their effects in vivo are less pronounced, while PPARα agonists show modest browning effects both in vitro or in vivo. In the present study, we investigated whether PPARα and PPARγ dual agonism would have synergistic effects in inducing browning of WAT. We found that all tested dual PPARα/γ agonists robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human preadipocytes, with tesaglitazar giving the largest Ucp1 induction. Notably, tesaglitazar also strongly induced browning of WAT in vivo in both lean and obese mice at thermoneutrality, largely exceeding the increase in Ucp1 observed with rosiglitazone. Mechanistically, we found that selective PPARγ agonism was sufficient for the conversion of white into brown-like adipocytes in vitro, but dual PPARα/γ agonism was superior to selective PPARγ agonism at inducing white fat browning in vivo, at least in part via a PPARα-mediated increase in fibroblast growth factor 21 (FGF-21). In human preadipocytes in vitro, combined treatment with rosiglitazone and FGF-21 resulted in a robust and synergistic increase in UCP1 mRNA levels, superior to rosiglitazone- or FGF-21-monotreatments. Tesaglitazar-induced browning in obese mice was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups. In conclusion, we found that dual PPARα/γ agonism robustly promotes browning of white fat in vivo, via synergistic action of FGF-21 and PPARγ agonism. Our findings identify a novel opportunity to develop compounds with robust browning of WAT, via dual modulation of PPARα and PPARγ. Disclosure T. Kroon: Employee; Self; AstraZeneca. M.J. Harms: Employee; Self; AstraZeneca. D. Nilsson: None. A. Lindblom: Employee; Self; AstraZeneca. P. Gennemark: Employee; Self; AstraZeneca. G. O'Mahony: Employee; Self; AstraZeneca. V. Osinski: None. C.A. McNamara: None. J. Boucher: Employee; Self; AstraZeneca.