Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPARa and insulin-dependent signaling in hepatocytes

Sarra Smati (1) , Marion Régnier (1) , Tiffany Fougeray (2) , Arnaud Polizzi (2) , Anne Fougerat (2) , Frédéric Lasserre (2) , Céline Lukowicz (1) , Blandine Tramunt (3) , Maeva Guillaume (3) , Anne-Francoise Burnol (4) , Catherine Postic (4) , Walter Wahli (1, 5, 6) , Alexandra Montagner (3) , Pierre Gourdy (3, 7) , Hervé Guillou (2)

1 ToxAlim - ToxAlim
2 ToxAlim-TIM - Toxicologie Intégrative & Métabolisme
3 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 Nanyang Technological University [Singapour]
6 CIG - Center for Integrative Genomics - Institute of Bioinformatics, Génopode
7 Service Diabétologie [CHU Toulouse]

Aim.-In hepatocyte, PPARa and insulin receptor (IR) are critical for the transcriptional responses to fasting and feeding, respectively. Here we analyzed the effects of the nutritional status (fasting vs feeding) on the expression of a large panel of hepatokines in hepatocyte-specific PPARa (Ppara hep−/−) and IR (IR hep−/−) null mice. Methods.-Ppara hep−/− , and IR hep−/− mice and their wild-type littermate were subjected to fasting or feeding metabolic challenges, and then analyzed for hepatokine gene expression. Experiments were conducted in mice of both sexes. 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.

Mots clés: Nutritional regulation; PPAR-alpha; Hepatokines; Insulin receptor

Domaines: Sciences du Vivant [q-bio]; Biochimie, Biologie Moléculaire

Sarra Smati, Marion Régnier, Tiffany Fougeray, Arnaud Polizzi, Anne Fougerat, et al.. Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPARa and insulin-dependent signaling in hepatocytes. Diabetes & Metabolism, 2020, 46 (2), pp.129-136. ⟨10.1016/j.diabet.2019.05.005⟩. ⟨hal-02402566⟩