In an ever-changing environment where food availability is highly unpredictable, the ability to maintain energy homeostasis requires proper sensing of dietary macronutrients, and subsequent adaptive adjustments in feeding behavior. Cholesterol is an important macronutrient, but cytotoxic in excess. Thus, cholesterol metabolism is under tight homeostatic regulation. Cholesterol is a major precursor of bile acids. After a meal, bile acids are released into the intestine and stimulate the secretion of fibroblast growth factor 15/19 (FGF-15/19). FGF-15/19 is an enterokine known to specifically suppress Agouti-related protein (AgRP), a neuropeptide of the central melanocortin system (CMS) that increases with fasting and promotes feeding and locomotor activity. Studies show that the CMS plays a modulatory role in hepatic cholesterol metabolism. However, the effects of dietary cholesterol on feeding behavior and energy homeostasis have remained largely unexplored. In this study, we found, surprisingly, that dietary cholesterol modulates expression of AgRP. Specific removal of cholesterol from the diets of wild type mice under ad-lib conditions leads to increased hypothalamic Agrp, but not Npy, mRNA expression. Furthermore, these mice also have low intestinal fGF-15mRNA expression. Cholesterol deficiency also leads to increased locomotor activities, an effect that is AgRP dependent as locomotor activity in AgRP knockout mice is unaffected by alterations in dietary cholesterol content. In wild type mice, fasting induces increased locomotor activity, which is widely thought to be a proxy for food seeking behavior. Notably, we observe dietary cholesterol content has no effect on ad-libfood intake, suggesting food seeking behaviors may be uncoupled from food intake. Taken together, these results suggest a novel paradigm where dietary cholesterol can act as a peripheral nutrient signal that can ultimately affect locomotor activity and possibly food seeking behavior.
A. Huang: None. M.T. Maier: None. A. Xu: None.