Intestinal FXR agonism synergizes with leptin to improve obesity by reducing appetite via secretin

Abstract Obesity is a chronic condition and is closely associated with various metabolic diseases. It has become a global health concern, and effective pharmacotherapies are urgently needed. Farnesoid X receptor (FXR) is widely regarded as a pivotal target for the treatment of metabolic diseases because of its many biological functions. To avoid the possible adverse side effects of systemic FXR agonism, intestinal-specific FXR agonists have been developed. They show excellent anti-obesity effects, but the underlying mechanism remains unclear. In this study, we demonstrate that intestinal-restricted FXR agonists exhibit marked anti-obesity effects in diet-induced obesity (DIO) and db/db mice, but not in ob/ob mice. Mechanistically, they suppress appetite to reduce obesity in leptin-dependent and secretin-dependent manners. Intestinal FXR agonism upregulates secretin (SCT) expression in the presence of leptin. Specifically, FXR agonism enhances histone H3K4 methylation at the Sct locus, while leptin per se suppresses DNA methylation at the same locus in a leptin-receptor independent manner. Collectively, the results of this study clarify the anti-obesity mechanism underlying intestinal FXR agonists.