1. PGC-1β: A Regulator of Mitochondrial Function with Subtle Roles in Energy Metabolism
- Author
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Adrienn Kis, Mark Campbell, Mohammad Bohlooly-Y, Keira Curtis, Barbara Cannon, Matej Orešič, E. Dale Abel, Vlad G. Zaha, Gema Medina-Gomez, Sheldon E. Litwin, Mercedes Jimenez-Linan, Antonio Vidal-Puig, Sihem Boudina, Kimberly T Fountain, Leonard H Storlien, Miguel López, Margaret Blount, Ping Hu, Helena M. Feldmann, Christopher J. Lelliott, Mikael Bjursell, Natasa Petrovic, Dongfang Zhang, Nadeene Parker, Maria Strömstedt, Aline Meirhaeghe, Michael Snaith, Autard, Delphine, Department of Clinical Biochemistry, University of Cambridge [UK] (CAM), AstraZeneca, The Wenner-Gren Institute, Stockholm University, Division of Cardiology, University of Utah, Division of Endocrinology, Metabolism, and Diabetes, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Technical Research Centre of Finland, VTT Technical Research Centre of Finland (VTT), 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), and 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).
- Subjects
Male ,MESH: Cold Temperature ,Adipose tissue ,White adipose tissue ,Mitochondrion ,MESH: Mice, Knockout ,Mitochondria, Heart ,chemistry.chemical_compound ,Mice ,Norepinephrine ,0302 clinical medicine ,Adipose Tissue, Brown ,Heart Rate ,Brown adipose tissue ,Body Fat Distribution ,Diabetes/Endocrinology/Metabolism ,MESH: Thermogenesis ,MESH: Animals ,Biology (General) ,MESH: Heart Rate ,Mice, Knockout ,Mammals ,0303 health sciences ,MESH: Muscle, Skeletal ,General Neuroscience ,MESH: Energy Metabolism ,Heart ,Thermogenesis ,Mus (Mouse) ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,MESH: Gene Expression Regulation ,Mitochondria ,Cold Temperature ,medicine.anatomical_structure ,Liver ,MESH: Adipose Tissue, White ,Synopsis ,Female ,MESH: Mitochondria, Heart ,General Agricultural and Biological Sciences ,Metabolic Networks and Pathways ,Research Article ,MESH: Electron Transport Chain Complex Proteins ,medicine.medical_specialty ,QH301-705.5 ,MESH: Mitochondria ,MESH: Trans-Activators ,Adipose Tissue, White ,Biology ,MESH: Diet, Atherogenic ,MESH: Adipose Tissue, Brown ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Adrenergic Agents ,Internal medicine ,MESH: Norepinephrine ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,MESH: Body Fat Distribution ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Muscle, Skeletal ,MESH: Mice ,030304 developmental biology ,Soleus muscle ,General Immunology and Microbiology ,Triglyceride ,Body Weight ,medicine.disease ,MESH: Adrenergic Agents ,MESH: Male ,MESH: Body Weight ,MESH: Heart ,Endocrinology ,chemistry ,Electron Transport Chain Complex Proteins ,Gene Expression Regulation ,MESH: Metabolic Networks and Pathways ,Trans-Activators ,Diet, Atherogenic ,Steatosis ,Energy Metabolism ,MESH: Female ,030217 neurology & neurosurgery ,Transcription Factors ,MESH: Liver - 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., The authors conduct an in-depth analysis of a PGC-1β knockout mouse; these animals posses specific defects in basal mitochondrial function and adaptation to metabolic stress.
- Published
- 2006