Pregnane X receptor deletion induces a lean phenotype in chow-fed mice through a liver-ileum-muscle axis involving 6α-hydroxylated bile acids and Fgf15.

OBJECTIVES: The pregnane X receptor (Pxr; Nr1i2) plays a role in metabolic regulation. However, its contribution to systemic energy homeostasis under physiological conditions remains unclear. Here, we investigated the metabolic consequences of Nr1i2 deficiency in chow-fed mice. METHODS: Phenotyping was performed in adult whole-body Nr1i2 knockout (Nr1i2-/-) chow-fed mice and their wild-type littermates. Body composition, metabolic parameters, skeletal muscle mass and myofiber size were assessed. Ileal gene expression, circulating Fgf15 levels, and bile acid composition were analyzed. Intestinal-specific Nr1i2-/- mice were generated to evaluate the contribution of intestinal Pxr signaling. Mechanistic studies were conducted in HT29 cells and mouse ileal organoids. RESULTS: Chow-fed Nr1i2-/- mice displayed a lean phenotype with reduced adiposity, improved insulin sensitivity, and increased skeletal muscle mass and myofiber size compared with wild-type mice. This phenotype was associated with strong induction of ileal Fgf15 gene expression and elevated circulating Fgf15 levels. Intestinal-specific Nr1i2 deletion did not reproduce the metabolic or muscular phenotype, indicating that intestinal Pxr loss alone is insufficient. Nr1i2 deficiency was associated with remodeling of the hepatic bile acid pathway and enrichment of specific taurine-conjugated and 6α-hydroxylated bile acids in the ileum. In vitro, these bile acids enhanced FGF19 expression through FXR-related canonical and non-canonical mechanisms, supporting a mechanistic link between bile acid remodeling and increased Fgf15/19 signaling. CONCLUSIONS: These findings provide the first evidence that, under standard dietary conditions, loss of Pxr induces a lean phenotype, promotes reduced adiposity together with remodeling of bile acid pool, increased Fgf15 production and enhanced skeletal muscle mass.