Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPAR-α and insulin-dependent signalling in hepatocytes

In hepatocytes, the peroxisome proliferator-activated receptor (PPAR)-α and insulin receptor (IR) are critical for transcriptional responses to fasting and feeding, respectively. The present report analyzes the effects of nutritional status (fasting vs feeding) on the expression of a large panel of hepatokines in hepatocyte-specific PPAR-α (Pparα hep−/−) and IR (IRhep−/−) null mice. Pparαhep−/− and IRhep−/− mice, and their wild-type littermates, were subjected to fasting or feeding metabolic challenges, then analyzed for hepatokine gene expression. Experiments were conducted in mice of both genders. Our data confirmed that PPAR-α is essential for regulating fasting-induced Fgf21 and Angptl4 expression. In mice lacking PPAR-α, fasting led to increased Igfbp1 and Gdf15 gene expression. In the absence of hepatic IR, feeding induced overexpression of Igfbp1, follistatin (Fst) and adropin (Enho), and reduced activin E (Inhbe) expression. Gender had only a modest influence on hepatokine gene expression in the liver. The present results highlight the potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both female and male mice.