Peroxisome proliferator-activated receptor-alpha modulates insulin gene transcription factors and inflammation in adipose tissues in mice.

We have recently reported that PPAR alpha deficiency leads to hypoglycaemia and hypoinsulinemia in mice (Yessoufou et al. Endocrinology 147:4410-4418, 2006). Besides, these mice exhibited high adiposity with an inflammatory state. We, therefore, assessed, in this study, the effects of PPAR alpha deficiency on the expression of mRNA encoding for the insulin gene transcription factors in pancreatic beta-cells along with those implicated in inflammation in adipose tissues. On fasting, the adult PPAR alpha-null mice were hypoglycemic. Serum insulin concentrations and its pancreatic mRNA transcripts were downregulated in PPAR alpha-null mice, suggesting that PPAR alpha gene deletion contributes to low insulin gene transcription. The PPAR alpha gene deletion downregulates the mRNA expression of insulin gene transcription factors, i.e., Pdx-1, Nkx6.1, and MafA. Besides, the pancreatic function was diminished by PPAR alpha deficiency as PPAR alpha-null mice expressed low pancreatic Glut2 and glucokinase mRNA. PPAR alpha-null mice also expressed high adiponectin and leptin mRNA levels compared to wild type animals. Adipose tissues of PPAR alpha-null mice exhibited upregulation of CD14 and CD68 mRNA, generally expressed by macrophages. PPAR alpha gene deletion downregulates the adipocyte mRNA of certain pro-inflammatory agents, like MCP-1, TNF-alpha, IL-1 beta, IL-6, and RANTES, though pro-inflammatory TLR-2 and TLR-4 mRNAs were upregulated in the adipose tissues. Our results suggest that PPAR alpha deficiency, in mice, is implicated in the modulation of insulin gene transcription and inflammatory status in adipose tissues.