Teresa C Leone 1 , 2 , John J Lehman 1 , 2 , Brian N Finck 1 , 2 , Paul J Schaeffer 1 , 2 , Adam R Wende 1 , 2 , Sihem Boudina 3 , Michael Courtois 1 , 2 , David F Wozniak 4 , Nandakumar Sambandam 1 , 2 , Carlos Bernal-Mizrachi 1 , 2 , Zhouji Chen 2 , John O. Holloszy 2 , Denis M Medeiros 5 , Robert E Schmidt 6 , Jeffrey E Saffitz 1 , 6 , E. Dale Abel 3 , Clay F Semenkovich 1 , 2 , Daniel P Kelly , 1 , 2 , 7 , 8
15 March 2005
The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α −/−) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α −/− mice. With age, the PGC-1α −/− mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α −/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α −/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α −/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α −/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α −/− mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α −/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.
Eliminating the activity of the gene PGC-1 α in mice reveals its role in post-natal metabolism and provides a link to obesity and some intriguing differences with another report of this knockout