Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

Abstract

The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.

Immunologic impact of the intestine in metabolic disease

“…The LXR reduces Th17 lineage differentiation (46), as this effect competes with endogenous oxysterol ligands for RORγt (47) while gut-specific targeting of the FXR exerts antiinflammatory effects (48). A fat-enriched diet also reduces the number of ileal IL-17/RORγt CD4 + T cells, and IL-17/RORγt-deficient T cells are associated with the induction of glucose intolerance and obesity (49).…”

Obesity diabetes and the role of bile acids in metabolism

“…They showed that a deficiency of 12 α-hydroxylated bile acids and their synthetic enzyme CYP8B1 hinder the triglyceride, lowering effects of FXR. More recently, Fang et al [14] have shown that the bile acid release during a meal activates intestinal FXR. Up-regulating FXR with an intestinal agonist reduced diet-induced weight gain and hepatic glucose production while enhancing thermogenesis and browning of white adipose tissue.…”

“…Bile acids are increased after bariatric surgery, but not after a hypocaloric diet [31] . The exciting work by Fang et al [14] shows that the bile acid release during a meal selectively activates the intestinal FXR. They showed that the intestinal FXR agonist fexaramine induces FGF 15, leading to alterations in bile acid composition, reduced diet-induced weight gain, and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue.…”

Horizons in the Pharmacotherapy of Obesity

“…Recently, the gut-restricted FXR agonist fexaramine has been reported to reduce obesity and insulin resistance in mice. These effects are associated with browning of adipose tissue [84], which raises the possibility that fexaramine increases sympathetic activity.…”