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

Aim. - In hepatocytes, the peroxisome proliferator-activated receptor (PPAR)-alpha 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-alpha (Ppar alpha(hep-/-)) and IR (IRhep-/-) null mice. Methods. - Ppar alpha(hep-/-) 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. Results. - Our data confirmed that PPAR-alpha is essential for regulating fasting-induced Fgf21 and Angptl4 expression. In mice lacking PPAR-alpha, 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. Conclusion. - 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. (C) 2019 Elsevier Masson SAS. All rights reserved.