Aims/hypothesis: The coactivator of nuclear receptors, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) 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-1α antisense oligonucleotide (PGC-1αAS) that inhibits up to 60% of PGC-1α 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-1αAS 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-1αAS 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. 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