title: Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance.
abstract: 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.
authors.affiliation: Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lelliott
authors.forename: Gema
authors.initials: G
authors.lastname: Medina-Gomez
authors.forename: Natasa
authors.initials: N
authors.lastname: Petrovic
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kis
authors.forename: Helena M
authors.initials: HM
authors.lastname: Feldmann
authors.forename: Mikael
authors.initials: M
authors.lastname: Bjursell
authors.forename: Nadeene
authors.initials: N
authors.lastname: Parker
authors.forename: Keira
authors.initials: K
authors.lastname: Curtis
authors.forename: Mark
authors.initials: M
authors.lastname: Campbell
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: Dongfang
authors.initials: D
authors.lastname: Zhang
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: Vlad G
authors.initials: VG
authors.lastname: Zaha
authors.forename: Kimberly T
authors.initials: KT
authors.lastname: Fountain
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Mercedes
authors.initials: M
authors.lastname: Jimenez-Linan
authors.forename: Margaret
authors.initials: M
authors.lastname: Blount
authors.forename: Miguel
authors.initials: M
authors.lastname: Lopez
authors.forename: Aline
authors.initials: A
authors.lastname: Meirhaeghe
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
authors.forename: Leonard
authors.initials: L
authors.lastname: Storlien
authors.forename: Maria
authors.initials: M
authors.lastname: Strömstedt
authors.forename: Michael
authors.initials: M
authors.lastname: Snaith
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannon
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology; D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D050218:Body Fat Distribution; D001835:Body Weight; D003080:Cold Temperature; D004036:Diet, Atherogenic; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D008099:Liver / Q000502:physiology*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D008929:Mitochondria, Heart; D018482:Muscle, Skeletal / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D018663:Adrenergic Agents; D045222:Electron Transport Chain Complex Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D009638:Norepinephrine