Peroxisome proliferator-activated receptorγ coactivators (PGC-1α and PGC-1β) play important roles in the transcriptional regulation of intermediary metabolism. To evaluate the effects of overexpressing PGC-1α or PGC-1β at physiologic levels in liver, we generated transgenic mice with inducible overexpression of PGC-1α or PGC-1β. Gene expression array profiling revealed that whereas both PGC-1 family proteins induced mitochondrial oxidative enzymes, the expression of several genes involved in converting glucose to fatty acid was induced by PGC-1β, but not PGC-1α. The increased expression of enzymes involved in carbohydrate utilization and de novo lipogenesis by PGC-1β required carbohydrate response element binding protein (ChREBP). The interaction between PGC-1β and ChREBP, as well as PGC-1β occupancy of the liver-type pyruvate kinase promoter, was influenced by glucose concentration and liver-specific PGC-1β-/- hepatocytes were refractory to the lipogenic response to high glucose conditions. These data suggest that PGC-1β-mediated coactivation of ChREBP is involved in the lipogenic response to hyperglycemia.