[HTML][HTML] PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis

TC Leone, JJ Lehman, BN Finck, PJ Schaeffer… - PLoS …, 2005 - journals.plos.org
TC Leone, JJ Lehman, BN Finck, PJ Schaeffer, AR Wende, S Boudina, M Courtois…
PLoS biology, 2005journals.plos.org
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 …
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.
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