Sci. STKE, 12 October 2004
METABOLISM Aberrant Metabolism and Hyperactive Mice
PGC-1α [peroxisome proliferator-activated receptor (PPAR) coactivator-1α] is a coactivator for many transcription factors and has an established role in controlling metabolism, including mitochondrial respiration and gluconeogenesis. Lin et al. report that mice deficient in PGC-1α are resistant to diet-induced obesity despite having increased hepatic gluconeogenesis, aberrant brown fat with large lipid droplets, reduced oxygen consumption (a measure of mitochondrial respiration), and increased sensitivity to cold. In vivo, the aberrant hepatic gluconeogenesis appeared to be due to constitutive activation of the gluconeogenic pathway by excessive CAAT-enhancer-binding protein β (C/EPBβ), a transcription factor that is normally increased in abundance by fasting and that stimulates the expression of genes involved in glucose synthesis. The resistance to diet-induced obesity appeared to be due to hyperactivity of the mice. In addition, the mice exhibited several behavioral characteristics of neurological disorders. Histological analysis of the brains from the mutant mice showed spongiform lesions in the striatum and, to a lesser extent, in other brain regions, including the cortex, thalamus, and substantia nigra, which also contribute to control of movement. Analysis of gene expression (based on real-time PCR analysis) indicated not only that the expression of mitochondrial genes was reduced, but that the expression of several neuronal genes was also impaired. Cultured striatal neurons from the mutant mice showed reduced neurite growth and branching compared with cells from wild-type mice. Houten and Auwerx discuss these results and their implication for understanding metabolic disorders and neurodegenerative movement disorders.
J. Lin, P. H. Wu, P. T. Tarr, K. S. Lindenberg, J. St-Pierre, C. Y. Zhang, V. K. Mootha, S. Jager, C. R. Vianna, R. M. Reznick, L. Cui, M. Manieri, M. X. Donovan, Z. Wu, M. P. Cooper, M. C. Fan, L. M. Rohas, A. M. Zavacki, S. Cinti, G. I. Shulman, B. B. Lowell, D. Krainc, B. M. Spiegelman, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice. Cell 119, 121-135 (2004). [Online Journal]
S. M. Houten, J. Auwerx, PGC-1α: Turbocharging mitochondria. Cell 119, 5-7 (2004). [Online Journal]
Citation: Aberrant Metabolism and Hyperactive Mice. Sci. STKE 2004, tw363 (2004).
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