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Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5(+)) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal Farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5(+) cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5(+) cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

Summary: PGC1α is a pleiotropic co-factor that affects angiogenesis, mitochondrial biogenesis, and oxidative muscle remodeling via its association with multiple transcription factors, including the master oxidative nuclear receptor ERRγ. To decipher their epistatic relationship, we explored ERRγ gain of function in muscle-specific PGC1α/β double-knockout (PKO) mice. ERRγ-driven transcriptional reprogramming largely rescues muscle damage and improves muscle function in PKO mice, inducing mitochondrial biogenesis, antioxidant defense, angiogenesis, and a glycolytic-to-oxidative fiber-type transformation independent of PGC1α/β. Furthermore, in combination with voluntary exercise, ERRγ gain of function largely restores mitochondrial energetic deficits in PKO muscle, resulting in a 5-fold increase in running performance. Thus, while PGC1s can interact with multiple transcription factors, these findings implicate ERRs as the major molecular target through which PGC1α/β regulates both innate and adaptive energy metabolism. : Fan et al. demonstrate that ERRγ improves mitochondrial energy metabolism in PGC1α/β-deficient muscle through its direct activation of target genes. Such ERRγ-induced effects are further boosted in combination with exercise training, suggesting ERRs are the major transcriptional modulator through which PGC1α/β regulates both innate and adaptive energy metabolism. Keywords: ERR, estrogen related receptor, PGC1, mitochondria, muscle, exercise, vasculature, fatty acid oxidation, glycolysis, muscle damage

Management of energy stores is critical during endurance exercise, with a shift in substrate utilization from glucose towards fat being a hallmark of trained muscle. Here we show that this key metabolic adaptation is both dependent on muscle PPARδ and stimulated by PPARδ ligand. Furthermore, we find that muscle PPARδ expression positively correlates with endurance performance in BXD mouse reference populations. In addition to stimulating fatty acid metabolism in sedentary mice, PPARδ activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels PPARδ acts to delay the onset of hypoglycemia and extends running time by ~100 minutes in treated mice. Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies and unavoidably, the enhancement of athletic performance.