Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

Lelliott, Christopher J.; Medina-Gómez, Gema; Petrovič, Nataša; Kis, Anna; Feldmann, Helena M.; Bjursell, Mikael; Parker, Nadeene; Curtis, Keira; Campbell, Mark; Hu, Ping; Zhang, Dongfang; Litwin, Sheldon E.; Zaha, Vlad G.; Fountain, Kimberly; Boudina, Sihem; Jimenez-Liñan, Mercedes; Blount, Margaret; López, Miguel; Meirhaeghe, Aline; Bohlooly‐Y, Mohammad; Storlien, Leonard H; Strömstedt, Maria; Snaith, Michael; Orešič, Matej; Abel, E. Dale; Cannon, Barbara; Vidal-Puig, António

doi:10.1371/journal.pbio.0040369

Cited by 253 publications

(258 citation statements)

References 36 publications

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“…Similar data have been reported from cultures of brown adipocytes isolated from whole-body PGC-1α knockout mice (39). PGC-1α seems to be important for the induction of thermogenic genes in BAT on cold exposure, whereas PGC-1β may regulate basal mitochondrial gene expression or compensate for loss of PGC-1α (39)(40)(41). Subcutaneous IWAT was found to be the most sensitive adipose tissue to this loss of PGC-1α.…”

Section: Discussionsupporting

confidence: 80%

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

Kleiner

Mepani

Laznik

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

252

193

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Reduced peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression and mitochondrial dysfunction in adipose tissue have been associated with obesity and insulin resistance. Whether this association is causally involved in the development of insulin resistance or is only a consequence of this condition has not been clearly determined. Here we studied the effects of adipose-specific deficiency of PGC-1α on systemic glucose homeostasis. Loss of PGC-1α in white fat resulted in reduced expression of the thermogenic and mitochondrial genes in mice housed at ambient temperature, whereas gene expression patterns in brown fat were not altered. When challenged with a high-fat diet, insulin resistance was observed in the mutant mice, characterized by reduced suppression of hepatic glucose output. Resistance to insulin was also associated with an increase in circulating lipids, along with a decrease in the expression of genes regulating lipid metabolism and fatty acid uptake in adipose tissues. Taken together, these data demonstrate a critical role for adipose PGC-1α in the regulation of glucose homeostasis and a potentially causal involvement in the development of insulin resistance.glucose metabolism | mitochondrial gene expression | thermogenesis | cold exposure | type 2 diabetes

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Section: Discussionsupporting

confidence: 80%

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

Kleiner

Mepani

Laznik

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

252

193

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“…We observed that overexpression of Pgc-1β was able to drive a transcriptional programme that increased the capacity for mitochondrial substrate oxidation, improved antioxidant defences and partially protected against HFD-induced insulin resistance. Gain-and loss-of-function studies have shown that PGC-1β regulates the expression of genes involved in mitochondrial function and lipid metabolism [15,16,38,39]. However, although much is known about the physiological stimuli that increase PGC-1α content in muscle, the in vivo regulation of PGC-1β is less well understood.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

et al. 2011

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Aims/Hypothesis To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1β [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of dietinduced insulin resistance. Methods Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1β in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1β on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. Results Pgc-1β gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1β. In rats fed a HFD, increasing the levels of Pgc-1β partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. Conclusions Our data show that an increase in Pgc-1β expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.

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“…They increase mitochondrial energy production by inducing the expression of genes that regulate fatty acid oxidation and by increasing mitochondrial activity (Kamei et al, 2003;Lin et al, 2003;Meirhaeghe et al, 2003;St-Pierre et al, 2003). Moreover, mice lacking either PGC-1a or PGC-1b exhibit little to no effect on mitochondrial mass and respiration activity (Lin et al, 2004;Leone et al, 2005;Lelliott et al, 2006;Sonoda et al, 2007). However, RNAimediated down-regulation of PGC-1b in PGC-1a À/À preadipocyte lines additively inhibits mitochondrial respiration (Uldry et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

Sun

Feng

et al. 2012

Developmental Dynamics

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Background: Members of the PPARg coactivator-1 (PGC-1) family are central transcriptional coactivators that regulate cell metabolic processes ranging from mitochondrial biogenesis to oxidative respiration. PGC-1-related coactivator (PPRC1 or PRC), initially identified as a member of the PGC-1 family, is believed to regulate mitochondria biogenesis, respiration pathways, and cell proliferation. However, its physiological role is not clearly understood. Here, we investigate the biological functions of PPRC1 in vivo using PPRC1 deficient mice generated by gene targeting. Results: Homozygous deficient PPRC1 mice failed to form egg cylinders and died after implantation but before embryonic day 6.5, whereas mice heterozygous for PPRC1 were viable, fertile and indistinguishable from their wild-type littermates. Furthermore, PPRC1 mRNA was expressed at the embryonic stage before implantation and was rapidly upregulated during the first day of embryoid body formation. The PPRC1 mRNA was then subsequently down-regulated, although its precise function at this stage of development was unclear. Conclusions: This is the first study to suggest a nonredundant role for PPRC1 in mouse early embryonic development. Developmental Dynamics 241:975-983, 2012. V C 2012 Wiley Periodicals, Inc.Key words: embryonic lethality; gene targeting; PGC-1-related coactivator; PGC-1 family Key findings:Disruption of pprc1 gene causes peri-implantation embryonic lethality. Developmental deficiencies in pprc1 2/2 embryos occur during peri-implantation. In vitro culturing of pprc1 2/2 blastocysts is susceptible to growth retardation. PPRC1 mRNA is expressed during preimplantation embryonic development. PPRC1 mRNA is rapidly up-regulated during early embryoid body formation. Accepted 23 February 2012Developmental Dynamics ABBREVIATIONS PGC-1 PPARg coactivator-1 PPRC1 PGC-1-a-related coactivator protein BAT brown adipose tissue ICM inner cell mass TG trophoblast giant cells E3.5 embryonic day 3.5 ESC embryonic stem cell EB embryoid body

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Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

Cited by 253 publications

References 36 publications

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

Development of insulin resistance in mice lacking PGC-1α in adipose tissues

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

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