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- Transcriptional control of energy metabolism: studies on FXR and PGC-1áPublication . Correia, Jorge Miguel Pratas Camacho; Ribeiro, Vera; Ruas, Jorge L.Sedentary lifestyles, combined with an environment of caloric abundance, have led to a remarkable increase in the incidence of obesity and diabetes. The resistance to insulin action observed in type 2 diabetes is a complex and multifactorial metabolic disorder. Several factors have been implicated in the development of insulin resistance, including systemic low-grade inflammation and ectopic lipid accumulation. The transcriptional regulators FXR and PGC-1α have been shown to promote beneficial effects on energy metabolism, which can be explored to improve metabolic status in settings of insulin resistance. Here, we show that FXR regulates hepatic metabolism in an isoform-dependent manner. Expression of each human FXR variant in primary hepatocytes promoted robust and discrete changes in target gene expression. Importantly, expression of FXRα2 and FXRα4 decreased hepatocyte lipid accumulation and improved insulin sensitivity. Furthermore, FXRα2 expression increased fatty acid oxidation and β-hydroxybutyrate production. In line with these observations, we observed that FXR splicing was dynamically regulated in mouse liver in response to fasting and physical exercise, with an increase in the relative expression of FXRα2. In addition, FXR expression is elevated in white adipose tissue of skeletal muscle-specific PGC-1α1 transgenic mice (MCK-PGC-1α1) and regulates adipocyte expression of major lipolytic mediators. Finally, we show that PGC-1α1 promotes an anti-inflammatory biological response in skeletal muscle, repressing the classical NFκB pathway. MCK-PGC-1α1 mice have decreased IKKβ, p50 and p65 expression, which is accompanied by a strong increase in IκBα protein levels. Importantly, PGC-1α1 enhances insulin-stimulated glycogen synthesis in cultured myotubes upon pro-inflammatory stimulation. Taken together, our results suggest that FXRα2 and PGC-1α1 improve metabolic conditions implicated in the development of insulin resistance and therefore are attractive therapeutic targets for the treatment of obesityassociated metabolic disorders.