Peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1? expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1? promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1? expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1? mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1? expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1? and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1? and gluconeogenesis genes were reduced. ZLN005 increased fat oxidation and improved the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. Hyperglycemia and dyslipidemia also were ameliorated after treatment with ZLN005. Our results demonstrated that a novel small molecule selectively elevated the expression of PGC-1? in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes.