Fgf15, the rodent orthologue of human FGF19, is a hormone expressed in ileal enterocytes of the small intestine. It plays a crucial role in the bile acid-FXR-FGF15/19 signaling axis. Bile acids, upon reabsorption in the ileum and colon, activate the nuclear receptor Farnesoid X receptor (FXR) which forms a heterodimer with retinoid X receptor α (RXRα). This heterodimer in the distal ileum regulates Fgf15 production. Fgf15 then travels via the enterohepatic circulation to activate the hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex, regulating gene expression involved in cholesterol, bile acid, and lipid metabolism, as well as cell proliferation [1].

Intestine-derived Fgf15-knockout (FGF15INT-KO) mice studies showed that these mice had increased systemic bile acid levels but decreased cholesterol levels when exposed to an obesogenic diet, indicating that gut-derived Fgf15 plays a primary role in regulating bile acid and cholesterol metabolism. However, control and FGF15INT-KO mice gained similar body weight and adiposity and did not show genotype-specific differences in glucose, mixed meal, pyruvate, and glycerol tolerance, suggesting that intestinal Fgf15 is not essential for energy and glucose balance [2]. Mice lacking FGF15 did not develop cardiac hypertrophy in response to high-fat diet, isoproterenol, or cold exposure, with lower heart weight/tibia length ratio and cardiomyocyte area under hypertrophy-inducing conditions compared to wild-type mice, and down-regulation of genes involved in fatty acid metabolism, revealing an Fgf15-mediated gut-to-heart axis in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium [3].

In conclusion, Fgf15 is essential for regulating bile acid and cholesterol metabolism, and also plays a role in cardiac hypertrophy development. Gene knockout mouse models have been instrumental in uncovering these functions, providing insights into its potential as a therapeutic target for metabolic and cardiovascular diseases.