Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance.
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.
Lelliott
Christopher J
CJ
Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Medina-Gomez
Gema
G
Petrovic
Natasa
N
Kis
Adrienn
A
Feldmann
Helena M
HM
Bjursell
Mikael
M
Parker
Nadeene
N
Curtis
Keira
K
Campbell
Mark
M
Hu
Ping
P
Zhang
Dongfang
D
Litwin
Sheldon E
SE
Zaha
Vlad G
VG
Fountain
Kimberly T
KT
Boudina
Sihem
S
Jimenez-Linan
Mercedes
M
Blount
Margaret
M
Lopez
Miguel
M
Meirhaeghe
Aline
A
Bohlooly-Y
Mohammad
M
Storlien
Leonard
L
Strömstedt
Maria
M
Snaith
Michael
M
Oresic
Matej
M
Abel
E Dale
ED
Cannon
Barbara
B
Vidal-Puig
Antonio
A
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
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