PPARα is required for PPARδ action in regulation of body weight and hepatic steatosis in mice

Peroxisome proliferator activated receptors alpha (PPAR alpha) anddelta (PPAR delta) belong to the nuclear receptor superfamily. PPAR alpha. is a target of well established lipid-lowering drugs. PPAR delta (also known as PPAR beta/delta) has been investigated as a promising antidiabetic drug target; however, the evidence in the literature on PPAR delta effect on hepatic lipidmetabolism is inconsistent. Mice conditionally expressing human PPAR delta demonstrated pronounced weight loss and promoted hepatic steatosis when treated with GW501516 (PPAR alpha-agonist) when compared to wild type mice. This effect was completely absent in mice with either a dominant negative form of PPAR delta or deletion of the DNA binding domain of PPAR delta. This confirmed the absolute requirement for PPAR delta in the physiological actions of GW501516 and confirmed the potential utility against the human form of this receptor. Surprisingly the genetic deletion of PPAR alpha also abrogated the effect of GW501516 in terms of both weight loss and hepatic lipid accumulation. Also the levels of the PPAR alpha endogenous agonist 16:0/18:1-GPC were shown to be modulated by PPAR delta in wild type mice. Our results show that both PPAR alpha and PPAR delta receptors are essential for GW501516-driven adipose tissue reduction and subsequently hepatic steatosis, with PPAR alpha working downstream of PPAR delta