Aims/hypothesis: The coactivator of nuclear receptors, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) has been implicated in a series of events that contribute to the control of glucose metabolism. We have recently reported the use of a PGC-1 alpha antisense oligonucleotide (PGC-1 alpha AS) that inhibits up to 60% of PGC-1 alpha expression in pancreatic islets, leading to increased insulin secretion. This oligonucleotide was used in this study to try to ameliorate diet-induced type 2 diabetes in a genetically predisposed mouse strain (Swiss mice). Materials and methods: Glucose and insulin tolerance tests, euglycaemic-hyperinsulinaemic clamp, immunoprecipitation assays, immunoblotting assays and immunohistochemistry were used in this investigation. Results: Swiss mice became obese and overtly diabetic after 8 weeks of feeding with chow containing 24% saturated fat. One daily dose (1.0 nmol) of PGC-1 alpha AS significantly reduced glucose and increased insulin blood levels without affecting food intake and body weight. These effects were accompanied by a reduced area under the glucose curve during an intraperitoneal glucose tolerance test, an increased constant of glucose decay (K-itt) during an insulin tolerance test, and an increased glucose consumption rate during a euglycaemic-hyperinsulinaemic clamp. Moreover, mice treated with PGC-1 alpha AS presented an outstanding reduction of macroscopic and microscopic features of hepatic steatosis. These effects were accompanied by reduced expression or function of a series of proteins involved in lipogenesis. Conclusions/interpretation: PGC-1 alpha is an attractive target for pharmacological therapeutics in type 2 diabetes mellitus and diet-induced hepatic steatosis.48918601871