fexaramine and Obesity

Obesity and its associated diseases, including type 2 diabetes, have reached epidemic levels worldwide. However, available treatment options are limited and ineffective in managing the disease. There is therefore an urgent need for the development of new pharmacological solutions. The bile acid (BA) Farnesoid X receptor (FXR) has recently emerged as an attractive candidate. Initially described for their role in lipid and vitamin absorption from diet, BAs are hormones with powerful effects on whole body lipid and glucose metabolism. In this review, we focus on FXR and how 2 decades of work on this receptor, both in rodents and humans, have led to the development of drug agonists with potential use in humans for treatment of conditions ranging from obesity-associated diseases to BA dysregulation.

Topics: Animals; Benzene Derivatives; Bile Acids and Salts; Humans; Molecular Targeted Therapy; Obesity; Receptors, Cytoplasmic and Nuclear

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.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Benzene Derivatives; Bile Acids and Salts; Fibroblast Growth Factors; Glucose Clamp Technique; Insulin Resistance; Intestinal Mucosa; Mice; Obesity; Receptors, Cytoplasmic and Nuclear; Weight Gain

Topics: Adipose Tissue, Brown; Animals; Benzene Derivatives; Bile Acids and Salts; Fibroblast Growth Factors; Insulin Resistance; Intestinal Mucosa; Obesity; Receptors, Cytoplasmic and Nuclear; Weight Gain