The hepatocyte insulin receptor is required to program rhythmic gene expression and the liver clock

• DOI: 10.1101/2021.02.05.430014
• Publication Date: 2021-02-08T04:15:12Z
• Authors: Tiffany Fougeray; Arnaud Polizzi; Marion Régnier; Anne Fougerat; Sandrine Ellero-S...; Yannick Lippi; Sarra Smati; Frédéric Lasserre; Blandine Tramunt; Marine Huillet; Léonie Dopavogui; Lorraine Smith; Claire Naylies; Caroline Sommer; Alexandre Benani; Joel T. Haas; Walter Wahli; Hélène Duez; Pierre Gourdy; Laurence Gamet-Pa...; Anne-Françoise Bu...; Nicolas Loiseau; Catherine Postic; Alexandra Montagner; Hervé Guillou
• Keywords: 2. Zero hunger; 0303 health sciences; 03 medical and health sciences

SUMMARYIn mammalian cells, gene expression is rhythmic and sensitive to various environmental and physiological stimuli. A circadian clock system helps to anticipate and synchronize gene expression with daily stimuli including cyclic light and food intake, which control the central and peripheral clock programs, respectively. Food intake also regulates insulin secretion. How much insulin contributes to the effect of feeding on the entrainment of the clock and rhythmic gene expression remains to be investigated.An important component of insulin action is mediated by changes in insulin receptor (IR)-dependent gene expression. In the liver, insulin at high levels controls the transcription of hundreds of genes involved in glucose homeostasis to promote energy storage while repressing the expression of gluconeogenic genes. In type 2 diabetes mellitus (T2DM), selective hepatic insulin resistance impairs the inhibition of hepatic glucose production while promoting lipid synthesis. This pathogenic process promoting hyperlipidemia as well as non-alcoholic fatty liver diseases.While several lines of evidence link such metabolic diseases to defective control of circadian homeostasis, the hypothesis that IR directly synchronizes the clock has not been studiedin vivo. Here, we used conditional hepatocyte-restricted gene deletion to evaluate the role of IR in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in adult mouse liver.