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

Christopher J. Lelliott, 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-Linan, Margaret Blount, Miguel Lopez, Aline Meirhaeghe, Mohammad Bohlooly-YLeonard Storlien, Maria Strömstedt, Michael Snaith, Matej Orešič, E. Dale Abel, Barbara Cannon, Antonio Vidal-Puig

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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.
Original languageEnglish
Pages (from-to)2042-2056
JournalPLoS Biology
Volume4
Issue number11
DOIs
Publication statusPublished - 2006
MoE publication typeA1 Journal article-refereed

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Thermogenesis
liver function
heat production
Ablation
Tissue
White Adipose Tissue
receptors
Brown Adipose Tissue
Liver
white adipose tissue
Skeletal Muscle
brown adipose tissue
Fats
mice
Muscle
Mitochondrial Size
Physiological Stress
Dobutamine
Systems Biology
Dietary Fats

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Lelliott, C. J., Medina-Gomez, G., Petrovic, N., Kis, A., Feldmann, H. M., Bjursell, M., ... Vidal-Puig, A. (2006). Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biology, 4(11), 2042-2056. https://doi.org/10.1371/journal.pbio.0040369
Lelliott, Christopher J. ; Medina-Gomez, Gema ; Petrovic, Natasa ; Kis, Adrienn ; Feldmann, Helena M. ; Bjursell, Mikael ; Parker, Nadeene ; Curtis, Keira ; Campbell, Mark ; Hu, Ping ; Zhang, Dongfang ; Litwin, Sheldon E. ; Zaha, Vlad G. ; Fountain, Kimberly T. ; Boudina, Sihem ; Jimenez-Linan, Mercedes ; Blount, Margaret ; Lopez, Miguel ; Meirhaeghe, Aline ; Bohlooly-Y, Mohammad ; Storlien, Leonard ; Strömstedt, Maria ; Snaith, Michael ; Orešič, Matej ; Abel, E. Dale ; Cannon, Barbara ; Vidal-Puig, Antonio. / Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. In: PLoS Biology. 2006 ; Vol. 4, No. 11. pp. 2042-2056.
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title = "Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance",
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.",
author = "Lelliott, {Christopher J.} and Gema Medina-Gomez and Natasa Petrovic and Adrienn Kis and Feldmann, {Helena M.} and Mikael Bjursell and Nadeene Parker and Keira Curtis and Mark Campbell and Ping Hu and Dongfang Zhang and Litwin, {Sheldon E.} and Zaha, {Vlad G.} and Fountain, {Kimberly T.} and Sihem Boudina and Mercedes Jimenez-Linan and Margaret Blount and Miguel Lopez and Aline Meirhaeghe and Mohammad Bohlooly-Y and Leonard Storlien and Maria Str{\"o}mstedt and Michael Snaith and Matej Orešič and Abel, {E. Dale} and Barbara Cannon and Antonio Vidal-Puig",
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Lelliott, CJ, Medina-Gomez, G, Petrovic, N, Kis, A, Feldmann, HM, Bjursell, M, Parker, N, Curtis, K, Campbell, M, Hu, P, Zhang, D, Litwin, SE, Zaha, VG, Fountain, KT, Boudina, S, Jimenez-Linan, M, Blount, M, Lopez, M, Meirhaeghe, A, Bohlooly-Y, M, Storlien, L, Strömstedt, M, Snaith, M, Orešič, M, Abel, ED, Cannon, B & Vidal-Puig, A 2006, 'Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance', PLoS Biology, vol. 4, no. 11, pp. 2042-2056. https://doi.org/10.1371/journal.pbio.0040369

Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. / Lelliott, Christopher J.; Medina-Gomez, Gema; Petrovic, Natasa; Kis, Adrienn; Feldmann, Helena M.; Bjursell, Mikael; Parker, Nadeene; Curtis, Keira; Campbell, Mark; Hu, Ping; Zhang, Dongfang; Litwin, Sheldon E.; Zaha, Vlad G.; Fountain, Kimberly T.; Boudina, Sihem; Jimenez-Linan, Mercedes; Blount, Margaret; Lopez, Miguel; Meirhaeghe, Aline; Bohlooly-Y, Mohammad; Storlien, Leonard; Strömstedt, Maria; Snaith, Michael; Orešič, Matej; Abel, E. Dale; Cannon, Barbara; Vidal-Puig, Antonio.

In: PLoS Biology, Vol. 4, No. 11, 2006, p. 2042-2056.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance

AU - Lelliott, Christopher J.

AU - Medina-Gomez, Gema

AU - Petrovic, Natasa

AU - Kis, Adrienn

AU - Feldmann, Helena M.

AU - Bjursell, Mikael

AU - Parker, Nadeene

AU - Curtis, Keira

AU - Campbell, Mark

AU - Hu, Ping

AU - Zhang, Dongfang

AU - Litwin, Sheldon E.

AU - Zaha, Vlad G.

AU - Fountain, Kimberly T.

AU - Boudina, Sihem

AU - Jimenez-Linan, Mercedes

AU - Blount, Margaret

AU - Lopez, Miguel

AU - Meirhaeghe, Aline

AU - Bohlooly-Y, Mohammad

AU - Storlien, Leonard

AU - Strömstedt, Maria

AU - Snaith, Michael

AU - Orešič, Matej

AU - Abel, E. Dale

AU - Cannon, Barbara

AU - Vidal-Puig, Antonio

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pbio.0040369

DO - 10.1371/journal.pbio.0040369

M3 - Article

VL - 4

SP - 2042

EP - 2056

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 11

ER -