PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis

Abstract

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.

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

“…PGC-1a also triggers mitochondrial biogenesis in skeletal and cardiac muscle 14,15 . Consistent with these findings, PGC-1a deficiency leads to multi-organ metabolic defects, including obesity, cold intolerance, hepatic steatosis, glucose imbalance and muscle dysfunction 16,17 .…”

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

“…They increase mitochondrial energy production by inducing the expression of genes that regulate fatty acid oxidation and by increasing mitochondrial activity (Kamei et al, 2003;Lin et al, 2003;Meirhaeghe et al, 2003;St-Pierre et al, 2003). Moreover, mice lacking either PGC-1a or PGC-1b exhibit little to no effect on mitochondrial mass and respiration activity (Lin et al, 2004;Leone et al, 2005;Lelliott et al, 2006;Sonoda et al, 2007). However, RNAimediated down-regulation of PGC-1b in PGC-1a À/À preadipocyte lines additively inhibits mitochondrial respiration (Uldry et al, 2006).…”

Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1α

“…This elevation of G6pc and Pepck expression was potentially caused by elevated hepatic C/ebpβ (also known as Cebpb) gene expression [8]. In contrast, in their mice, Leone et al [9] observed euglycaemia in the fasted state with no elevation of G6pc, Pepck or C/ebpβ expression in the fed state and the same induction following fasting as seen in wild-type mice. The reasons for these differences are unclear.…”

“…The reasons for these differences are unclear. Interestingly, although Leone et al [9] observed no change in G6pc and Pepck expression and euglycaemia in the fasted state, HGP and gluconeogenic flux are altered in these mice as a consequence of altered tricarboxylic acid cycle flux [10]. In mice with a liver-specific deletion of the Pgc-1α gene, G6pc and Pepck expression were normal in the fed state but their induction by fasting was impaired [11].…”

“…Two groups of investigators have generated mice with a global deletion of the Pgc-1α gene. Both reported that the mice were viable, but had multisystem abnormalities that included diminished mitochondrial respiratory capacity, vacuolar lesions in the central nervous system and cold intolerance [8,9]. However, these groups reported variable effects of PGC-1α deletion on hepatic gluconeogenic gene expression and fasting blood glucose levels.…”