ABSTRACT Objective Modulation of bile acid (BA) structure is a potential strategy for obesity and metabolic disease treatment. BAs act not only as signaling molecules involved in energy expenditure and glucose homeostasis, but also as regulators of food intake. The structure of BAs, particularly the position of the hydroxyl groups of BAs impacts food intake partly by intestinal effects: (1) modulating the activity of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), which produces the anorexigenic bioactive lipid oleoylethanolamide (OEA), or (2) regulating lipid absorption and the gastric emptying-satiation pathway. We hypothesized that 16α-hydroxylated BAs uniquely regulate food intake, because of the long intermeal intervals in snake species in which these BAs are abundant. However, the effects of 16α-hydroxylated BAs in mammals are completely unknown, because 16α-hydroxylated BAs are not naturally found in mammals. To test the effect of 16α-hydroxylated BAs on food intake, we isolated the 16α-hydroxylated BA pythocholic acid from ball pythons ( Python regius ). Methods Pythocholic acid or deoxycholic acid (DCA) were given by oral gavage in mice. DCA is known to increase NAPE-PLD activity better than other mammalian BAs. We evaluated food intake, OEA levels and gastric emptying in mice. Results We successfully isolated pythocholic acid from ball pythons for experimental use. Pythocholic treatment significantly decreased food intake compared with DCA treatment, and this was associated with increased jejunal OEA, but no change in gastric emptying or lipid absorption. Conclusion The exogenous bile acid pythocholic acid is a novel regulator of food intake and the satiety signal OEA in the mouse intestine. Highlights Pythocholic acid decreases food intake. Pythocholic acid increases intestinal OEA and other fatty acid ethanolamides. The effects of pythocholic acid on OEA and hypophagia are greater than the effects of DCA. Pythocholic acid does not affect lipid absorption or gastric emptying.

The python-derived 16α-hydroxylated bile acid, pythocholic acid decreases food intake and increases jejunal fatty acid ethanolamides in mice