Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

Abstract

The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders.

Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs administered new generation lipid emulsions

“…Also, our data suggest that premature piglet tissues have the capacity to readily take up preformed DHA and EPA given parenterally, especially DHA uptake in the brain. Ceramide concentrations have been implicated in the development of obesity and NAFLD (47,48). It was therefore interesting to see the high concentration of ceramide in the IL emulsion and the lack of ceramide in OV.…”

β-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue

“…These results suggest that the specific microbiota composition in HFD-fed Klb -/-mice is not the primary cause of their resistance to DIO. Nevertheless, further studies are warranted to elucidate whether the specific microbiota observed in Klb -/-mice can impact host energy partitioning via changes in short-chain fatty acid production (43,44) or intestinal BA signaling (41,45,46). Hepatosteatosis (nonalcoholic fatty liver, NAFL) is a classic complication of obesity.…”

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Furthermore, treatment with a gut-specific FXR agonist, fexaramine, reduces diet-induced increases in hepatic glucose production in mice, likely due to a robust increase in FGF 15 (Fang et al 2015). In contrast, some studies suggest that intestinal inhibition of FXR may in fact be beneficial via a reduction in intestinally derived ceramides , Jiang et al 2015, or via increased GLP-1 signalling (Trabelsi et al 2015), warranting further research into FXR agonism/antagonism for the treatment of diabetes. Interestingly, it has also been proposed that FXR-mediated metabolic improvements are due to alterations of the gut microbiota (Ryan et al 2014).…”