Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance

Christopher J. Lelliott, Gema Medina-Gomez, Natasa Petrovic, Adrienn Kis, Helena M. Feldmann, Mikael Bjursell, Nadeene Parker, Keira Curtis, Mark Campbell, Ping Hu, Dongfang Zhang, Sheldon E. Litwin, Vlad G. Zaha, Kimberly T. Fountain, Sihem Boudina, Mercedes Jimenez-Linan, Margaret Blount, Miguel Lopez, Aline Meirhaeghe, Mohammad Bohlooly-YLeonard Storlien, Maria Strömstedt, Michael Snaith, Matej Orešič, E. Dale Abel, Barbara Cannon, Antonio Vidal-Puig

Research output: Contribution to journalArticle

198 Scopus citations

Abstract

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.

Original languageEnglish (US)
Pages (from-to)2042-2056
Number of pages15
JournalPLoS biology
Volume4
Issue number11
DOIs
StatePublished - Nov 1 2006

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Lelliott, C. J., Medina-Gomez, G., Petrovic, N., Kis, A., Feldmann, H. M., Bjursell, M., Parker, N., Curtis, K., Campbell, M., Hu, P., Zhang, D., Litwin, S. E., Zaha, V. G., Fountain, K. T., Boudina, S., Jimenez-Linan, M., Blount, M., Lopez, M., Meirhaeghe, A., ... Vidal-Puig, A. (2006). Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS biology, 4(11), 2042-2056. https://doi.org/10.1371/journal.pbio.0040369