Intestinal gluconeogenesis (IGN), in which glucose produced in the small intestine is released into the portal vein, has shown protective effects against diabetes and obesity by positively regulating glucose homeostasis and hepatic glucose production. These effects have now been investigated in mice independently of nutritional manipulation and show that IGN has beneficial effects on hepatic steatosis and the initiation of nonalcoholic fatty liver disease (NAFLD).

“We previously demonstrated that IGN, via the sensing of glucose by the gastrointestinal neural system, signals to brain regions regulating energy homeostasis,” explains lead author Gilles Mithieux. “Given the likely effect of IGN on the liver via brain–sympathetic–parasympathetic signalling, we considered the hypothesis of a beneficial action of IGN on hepatic steatosis and initiation of NAFLD.”

Credit: Haematoxylin and eosin staining of mouse liver tissue from wild-type mice (above) and mice with overexpression of intestinal glucose 6-phosphatase (below). Images courtesy of G. Mithieux, Institut national de la santé et de la recherche médicale, France.

The effects of IGN were previously demonstrated in mice in response to protein-enriched or fibre-enriched diets. “To avoid possible interference with effects of inducing nutrients that could be independent of IGN, we created a mouse model of activated IGN through overexpression of intestinal glucose 6-phosphatase (G6Pase), the key enzyme of gluconeogenesis, which was compared to wild-type mice and mice with intestine-specific knockout of G6Pase,” explains Mithieux.

The researchers found that mice on a hypercaloric diet and overexpressing IGN in the gut were protected against development of hepatic steatosis. “The protection related to a diminution of de novo lipogenesis gene expression and lipid import, which was associated with decreased liver inflammation and fibrosis and the development of hepatic sympathetic nerves,” reports Mithieux. Conversely, IGN-deficient mice on a standard starch-enriched diet exhibited increased hepatic triglyceride storage and lipogenesis, which was corrected by a portal glucose infusion mimicking IGN.

“Our data are proof of the concept that activation of G6Pase in the gut is sufficient to activate IGN and prevent serious obesity-associated complications, such as NALFD and diabetes,” concludes Mithieux. “This paves the way for future approaches of prevention or treatment of metabolic diseases, starting with the search of potential activators of G6Pase restricted to the intestine.” The team also plan to further investigate the mechanisms of the effects induced by IGN, such as the prevention of body weight gain.