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Mol Metab. 2014 May 28;3(5):531-43. doi: 10.1016/j.molmet.2014.05.005. eCollection 2014 Aug.

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

Author information

1
Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France ; University of Aleppo, Aleppo, Syria.
2
Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69008, France ; Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France.
3
Université de Lyon, Lyon, F-69008, France ; Université Lyon 1, Villeurbanne, F-69622, France ; Centre National de la Recherche Scientifique, UMR5023, Villeurbanne, F-69622, France.
4
INRA-ToxALim, Toulouse, F-31027, France.

Abstract

Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.

KEYWORDS:

Endogenous glucose production; Energy expenditure; Hepatokines; Liver; Obesity; Type 2 diabetes

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