Bile acid-mediated OEA-PPARa signaling in food intake regulation - PROJECT SUMMARY/ABSTRACT More than half of adults are considered obese or overweight in the U.S. One important risk factor for obesity or overweight is considered to be excessive food intake. Currently, only five drugs are approved by FDA as an anti-obesity drug. However, some adverse effects have been reported. Thus, a novel approach or complementary method is necessary for obesity and metabolic diseases. For this, modulation of bile acids (BAs) is expected to be a potential approach because BAs are involved in glucose homeostasis and energy expenditure. Previously, we reported that BAs act not only as signaling molecules involved in energy expenditure and glucose homeostasis but also as regulators of food intake in the intestine. The structure of BAs, particularly the position of the hydroxyl groups of BAs impacts food intake through 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. Our preliminary data show that 16α-hydroxylated BAs, pythocholic acid increased OEA and decreased food intake in mice. However, the role of pythocholic acid in mammals is not completely known because 16α-hydroxylated BAs are not naturally found in mammals. We will examine 1) a detailed hypophagic mechanism of pythocholic acid, 2) the interaction between 16α-hydroxylated BAs and NAPE-PLD, and 3) the effect of 16α- hydroxylated BAs producing enzymes for modification of BA composition in mice.
