The suppression of hepatic glucose production improves metabolism and insulin sensitivity in subcutaneous adipose tissue in mice

• Published in: Diabetologia Vol. 59; no. 12; pp. 2645 - 2653
• Main Authors: Casteras, Sylvie, Abdul-Wahed, Aya, Soty, Maud, Vulin, Fanny, Guillou, Hervé, Campana, Mélanie, Le Stunff, Hervé, Pirola, Luciano, Rajas, Fabienne, Mithieux, Gilles, Gautier-Stein, Amandine
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2016; Springer Nature B.V; Springer Verlag
• Subjects: Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; Animals; Body fat; Diabetes; Diet, High-Fat - adverse effects; Energy Metabolism - physiology; Enzymes; Fatty acids; Female; Fibroblasts; Glucose; Glucose - metabolism; Growth factors; Human Physiology; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Insulin-Secreting Cells - metabolism; Internal Medicine; Kinases; Laboratory animals; Life Sciences; Lipid Metabolism - physiology; Lipolysis; Liver - metabolism; Liver diseases; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoglycerides - metabolism; Obesity; Phosphatase; Proteins; Subcutaneous Fat - metabolism; France; Obesity; Adipose tissue; Glucose 6-phosphatase; Hepatic glucose production; Hepatokines; Liver; Insulin resistance; Fatty acids; Steatosis; hepatic glucose; hepatokines; fatty acids; production; liver; glucose 6-phosphatase; adipose tissue; steatosis; insulin resistance; obesity
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-016-4097-y

Aims/hypothesis Despite the strong correlation between non-alcoholic fatty liver disease and insulin resistance, hepatic steatosis is associated with greater whole-body insulin sensitivity in several models. We previously reported that the inhibition of hepatic glucose production (HGP) protects against the development of obesity and diabetes despite severe steatosis, thanks to the secretion of specific hepatokines such as fibroblast growth factor 21 (FGF21) and angiopoietin-related growth factor. In this work, we focused on adipose tissue to assess whether liver metabolic fluxes might, by interorgan communication, control insulin signalling in lean animals. Methods Insulin signalling was studied in the adipose tissue of mice lacking the catalytic subunit of glucose 6-phosphatase, the key enzyme in endogenous glucose production, in the liver (L- G6pc − /− mice). Morphological and metabolic changes in the adipose tissues were characterised by histological analyses, gene expression and protein content. Results Mice lacking HGP exhibited improved insulin sensitivity of the phosphoinositide 3-kinase/Akt pathway in the subcutaneous adipose tissue associated with a browning of adipocytes. The suppression of HGP increased FGF21 levels in lean animals, and increased FGF21 was responsible for the metabolic changes in the subcutaneous adipose tissue but not for its greater insulin sensitivity. The latter might be linked to an increase in the ratio of monounsaturated to saturated fatty acids released by the liver. Conclusions Our work provides evidence that HGP controls subcutaneous adipose tissue browning and insulin sensitivity through two pathways: the release of beneficial hepatokines and changes in hepatic fatty acids profile.