Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

• DOI: 10.1371/journal.pbio.0040369
• Publication Date: 2006-11-03T09:23:08Z
• Authors: Christopher J Lel...; 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-...; Margaret Blount; Miguel Lopez; Aline Meirhaeghe; Mohammad Bohlooly-Y; Leonard Storlien; Maria Strömstedt; Michael Snaith; Matej Orešič; E. Dale Abel; Barbara Cannon; Antonio Vidal-Puig
• Keywords: Male; 0301 basic medicine; FATTY-ACID OXIDATION; LIVER; QH301-705.5; PGC-1-ALPHA; Adipose Tissue, White; BIOGENESIS; ENERGY-METABOLISM; Mice; 03 medical and health sciences; Adrenergic Agents; INDUCIBLE COACTIVATOR; Adipose Tissue, Brown; Heart Rate; [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology; Animals; Body Fat Distribution; Biology (General); IN-VIVO; Mice, Knockout; Body Weight; Heart; MUSCLE; Mitochondria; Cold Temperature; MICE; Electron Transport Chain Complex Proteins; Gene Expression Regulation; Liver; RAT; Diet, Atherogenic; Female; Energy Metabolism; Metabolic Networks and Pathways; Research Article

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta) has been implicated in important metabolic processes. A mouse lacking PGC-1beta (PGC1betaKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1betaKO 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-1beta ablation was partially compensated by up-regulation of PGC-1alpha in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1betaKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1beta was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1betaKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1betaKO mice have impaired mitochondrial function. Lack of PGC-1beta 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-1beta plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.