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PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.

Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP - PLoS Biol. (2005)

Bottom Line: Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/-) mice, leading to reduced muscle performance and exercise capacity.Following short-term starvation, PGC-1alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes.These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

View Article: PubMed Central - PubMed

Affiliation: Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri, USA.

ABSTRACT
The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha (PGC-1alpha(-/-)) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha(-/-) mice. With age, the PGC-1alpha(-/-) mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/-) mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha(-/-) mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha(-/-) mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha(-/-) mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha(-/-) mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

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PGC-1α−/− Mice Exhibit an Abnormal Thermogenic Response(A) PGC-1α+/+ (n = 15) and PGC-1α−/− (n = 21) mice aged 28–37 d were subjected to cold (4 °C). Core rectal temperature was monitored over a 5-h period. The change in core temperature ± SEM is shown in the graph (left) as a function of time. * p < 0.05.(B) Representative Northern blot analysis (blot and gel at top) performed with RNA isolated from BAT to detect UCP-1 transcript at baseline (RT) and after 5 h of exposure to cold (4 °C) (UCP1). Ethidium bromide (Eth Br) staining of ribosomal RNA is shown as a control. Quantitative real-time RT-PCR for UCP-1 transcript is shown on the graph at the bottom. The values represent mean arbitrary units normalized to a 36B4 transcript (control).(C) Altered response to β3-adrenergic agonist. To evaluate the oxygen consumption (VO2) in response to the stimulation of BAT uncoupled respiration, the β3-adrenergic agonist BRL 37344 was administered to littermate PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) female mice followed by measurement of VO2 by indirect calorimetry. Mean ± SEM VO2 is shown. * p < 0.05.
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pbio-0030101-g006: PGC-1α−/− Mice Exhibit an Abnormal Thermogenic Response(A) PGC-1α+/+ (n = 15) and PGC-1α−/− (n = 21) mice aged 28–37 d were subjected to cold (4 °C). Core rectal temperature was monitored over a 5-h period. The change in core temperature ± SEM is shown in the graph (left) as a function of time. * p < 0.05.(B) Representative Northern blot analysis (blot and gel at top) performed with RNA isolated from BAT to detect UCP-1 transcript at baseline (RT) and after 5 h of exposure to cold (4 °C) (UCP1). Ethidium bromide (Eth Br) staining of ribosomal RNA is shown as a control. Quantitative real-time RT-PCR for UCP-1 transcript is shown on the graph at the bottom. The values represent mean arbitrary units normalized to a 36B4 transcript (control).(C) Altered response to β3-adrenergic agonist. To evaluate the oxygen consumption (VO2) in response to the stimulation of BAT uncoupled respiration, the β3-adrenergic agonist BRL 37344 was administered to littermate PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) female mice followed by measurement of VO2 by indirect calorimetry. Mean ± SEM VO2 is shown. * p < 0.05.

Mentions: PGC-1α has been implicated as an inducible regulator of mitochondrial respiratory uncoupling, an important source of heat production in BAT [2]. To determine whether PGC-1α is necessary for an appropriate thermogenic response, PGC-1α+/+ and PGC-1α−/− mice were subjected to cold exposure (4 °C) for a 5-h period while core body temperature was monitored. PGC-1α−/− mice exhibited a markedly abnormal drop in core temperature compared to the WT controls (Figure 6A). Specifically, the mean decline in core temperature was greater than 12 °C at the 5-h time point in PGC-1α−/− mice, compared to an approximately 3 °C decrement in PGC-1α+/+ controls. Although this thermogenic phenotype was consistently present in mice aged 28–37 d, it was absent in older mice (unpublished data).


PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.

Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP - PLoS Biol. (2005)

PGC-1α−/− Mice Exhibit an Abnormal Thermogenic Response(A) PGC-1α+/+ (n = 15) and PGC-1α−/− (n = 21) mice aged 28–37 d were subjected to cold (4 °C). Core rectal temperature was monitored over a 5-h period. The change in core temperature ± SEM is shown in the graph (left) as a function of time. * p < 0.05.(B) Representative Northern blot analysis (blot and gel at top) performed with RNA isolated from BAT to detect UCP-1 transcript at baseline (RT) and after 5 h of exposure to cold (4 °C) (UCP1). Ethidium bromide (Eth Br) staining of ribosomal RNA is shown as a control. Quantitative real-time RT-PCR for UCP-1 transcript is shown on the graph at the bottom. The values represent mean arbitrary units normalized to a 36B4 transcript (control).(C) Altered response to β3-adrenergic agonist. To evaluate the oxygen consumption (VO2) in response to the stimulation of BAT uncoupled respiration, the β3-adrenergic agonist BRL 37344 was administered to littermate PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) female mice followed by measurement of VO2 by indirect calorimetry. Mean ± SEM VO2 is shown. * p < 0.05.
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Related In: Results  -  Collection

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pbio-0030101-g006: PGC-1α−/− Mice Exhibit an Abnormal Thermogenic Response(A) PGC-1α+/+ (n = 15) and PGC-1α−/− (n = 21) mice aged 28–37 d were subjected to cold (4 °C). Core rectal temperature was monitored over a 5-h period. The change in core temperature ± SEM is shown in the graph (left) as a function of time. * p < 0.05.(B) Representative Northern blot analysis (blot and gel at top) performed with RNA isolated from BAT to detect UCP-1 transcript at baseline (RT) and after 5 h of exposure to cold (4 °C) (UCP1). Ethidium bromide (Eth Br) staining of ribosomal RNA is shown as a control. Quantitative real-time RT-PCR for UCP-1 transcript is shown on the graph at the bottom. The values represent mean arbitrary units normalized to a 36B4 transcript (control).(C) Altered response to β3-adrenergic agonist. To evaluate the oxygen consumption (VO2) in response to the stimulation of BAT uncoupled respiration, the β3-adrenergic agonist BRL 37344 was administered to littermate PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) female mice followed by measurement of VO2 by indirect calorimetry. Mean ± SEM VO2 is shown. * p < 0.05.
Mentions: PGC-1α has been implicated as an inducible regulator of mitochondrial respiratory uncoupling, an important source of heat production in BAT [2]. To determine whether PGC-1α is necessary for an appropriate thermogenic response, PGC-1α+/+ and PGC-1α−/− mice were subjected to cold exposure (4 °C) for a 5-h period while core body temperature was monitored. PGC-1α−/− mice exhibited a markedly abnormal drop in core temperature compared to the WT controls (Figure 6A). Specifically, the mean decline in core temperature was greater than 12 °C at the 5-h time point in PGC-1α−/− mice, compared to an approximately 3 °C decrement in PGC-1α+/+ controls. Although this thermogenic phenotype was consistently present in mice aged 28–37 d, it was absent in older mice (unpublished data).

Bottom Line: Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/-) mice, leading to reduced muscle performance and exercise capacity.Following short-term starvation, PGC-1alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes.These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

View Article: PubMed Central - PubMed

Affiliation: Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri, USA.

ABSTRACT
The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha (PGC-1alpha(-/-)) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha(-/-) mice. With age, the PGC-1alpha(-/-) mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/-) mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha(-/-) mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha(-/-) mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha(-/-) mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha(-/-) mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

Show MeSH
Related in: MedlinePlus