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

Lelliott, CJ; Medina-Gomez, G; Petrovic, N; Kis, A; Feldmann, HM; Bjursell, M; Parker, N; ... Vidal-Puig, A; + view all (2006) Ablation of PGC-1 beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLOS BIOL , 4 (11) , Article e369. 10.1371/journal.pbio.0040369. Green open access

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Abstract

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 beta ( PGC-1 beta) has been implicated in important metabolic processes. A mouse lacking PGC-1 beta ( PGC1 beta KO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1 beta KO 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-1 beta ablation was partially compensated by up-regulation of PGC-1 alpha in BAT and white adipose tissue ( WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1 beta KO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1 beta was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1 beta KO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1 beta KO mice have impaired mitochondrial function. Lack of PGC-1 beta 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-1 beta plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.

Type: Article
Title: Ablation of PGC-1 beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pbio.0040369
Publisher version: http://dx.doi.org/10.1371/journal.pbio.0040369
Language: English
Additional information: © 2006 Lelliott et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The work presented in this paper was supported by grants from the British Heart Foundation, Wellcome Trust Integrative Physiology, and Diabetes Wellness Research Foundation (to AVP lab); NIH grants RO1HL73167 and UO1HL70525 from the National Institutes of Health and the Ben and Iris Margolis Foundation (to EDA - Established Investigator of the American Heart Association). Support was from the European Union (DLARFID), the Swedish Research Council, and the Swedish Cancer Society (to BC lab).
Keywords: FATTY-ACID OXIDATION, INDUCIBLE COACTIVATOR, ENERGY-METABOLISM, IN-VIVO, LIVER, PGC-1-ALPHA, BIOGENESIS, MUSCLE, MICE, RAT
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/128305
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