A new compound reduces the weight of obese mice by acting on their intestinal cells, finds a study published in Nature Communications this week. The compound, called Gly-MCA, selectively limits the action of bile acid receptor FXR - an important regulator of energy metabolism - and may aid the development of new therapeutic approaches in obesity-related metabolic disorders.
Bile acids are secreted in the gut, where they bind to the FXR receptor in intestinal cells and perform various metabolic functions. The development of anti-obesity drugs targeting FXR is difficult because FXR signaling can have either beneficial or negative metabolic consequences, depending on the tissue in which FXR is expressed.
Frank Gonzalez and colleagues create a bile-acid-based drug that is resistant to degradation by gut bacteria and is taken up only in negligible amounts into the blood stream. This drug inhibits FXR only in intestinal cells and not in the liver, where concentrations are too low to have any effect on FXR. The authors treat five mice with Gly-MCA over several experiments and show that the drug reduced weight gain in obese mice and improved their metabolic functions.
They also find that the beneficial effects of Gly-MCA are due to increased energy expenditure as a result of increased heat production in so-called ‘beige’ fat cells, which in turn occurs as a consequence of reduced production of lipid molecules (called ceramides) in intestinal cells.
The authors propose that Gly-MCA is a promising candidate for the treatment of metabolic disorders and that their work in mice may aid development of human therapies.