Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) has been shown to regulate adaptive thermogenesis and glucose metabolism. Here we show that PGC-1α regulates triglyceride metabolism through both farnesoid X receptor (FXR)-dependent and -independent pathways. PGC-1α increases FXR activity through two pathways: (1) it increases FXR mRNA levels by coactivation of PPARγ and HNF4α to enhance FXR gene transcription; and (2) it interacts with the DNA-binding domain of FXR to enhance the transcription of FXR target genes. Ectopic expression of PGC-1α in murine primary hepatocytes reduces triglyceride secretion by a process that is dependent on the presence of FXR. Consistent with these in vitro studies, we demonstrate that fasting induces hepatic expression of PGC-1α and FXR and results in decreased plasma triglyceride levels in wild-type but not in FXR-null mice. Our data suggest that PGC-1α plays an important physiological role in maintaining energy homeostasis during fasting by decreasing triglyceride production/secretion while it increases fatty acid β-oxidation to meet energy needs.