A link between hepatic glucose production and peripheral energy metabolism via hepatokines.

International audienceABSTRACTType 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulinresistance of glucose uptake by peripheral tissues and increased endogenous glucose production.Here we report that the specific suppression of hepatic glucose production positively modulateswhole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatasethat is mandatory for endogenous glucose production. When they were fed a high fat/high sucrosediet, they resisted the development of diabetes and obesity due to the activation of peripheralglucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones likefibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepaticglucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapidrestoration of glucose and body weight controls. Therefore, hepatic glucose production is anessential lever for the control of whole-body energy metabolism during the development of obesityand diabetes