Defects in Adaptive Energy Metabolism with CNS-Linked Hyperactivity in PGC-1α Null Mice

Abstract

PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training

“…Mice The generation and phenotype of PGC-1α KO mice have been described previously (Lin et al 2004). The genotype of the offspring was assessed by determining the presence of either a wild type (WT)-or KO-specific DNA fragment after extraction of DNA from a tail piece by the phenol-chloroform/isoamyl method, amplification of fragments by PCR using specific primers and separation on an agarose gel.…”

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

“…However, instead of the expected impairment, G6pc and Pepck gene expression were surprisingly elevated in the fed state to a level equivalent to that in the fasted state. 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.…”

“…However, these groups reported variable effects of PGC-1α deletion on hepatic gluconeogenic gene expression and fasting blood glucose levels. Lin et al [8] observed hypoglycaemia in the fasted state and reduced HGP. However, instead of the expected impairment, G6pc and Pepck gene expression were surprisingly elevated in the fed state to a level equivalent to that in the fasted state.…”

“…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.…”