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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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Evidence for Tissue-Specific Growth Abnormalities and Mild Sex-Limited, Age-Dependent Obesity in PGC-1α−/− Mice(A) The bars represent total body weight for the ages indicated for male (left graph) and female (center graph) PGC-1α+/+ and PGC-1α−/− mice. The body weight (BW) of the 1-wk-old PGC-1α−/− mice was normalized to that of PGC-1α+/+ littermates, which was assigned a value of 100 (left axis). For the 3-, 18-, and 24-wk time points, absolute weights of PGC-1α−/− mice were compared to age-matched controls (right axis). Percent fat as determined by DEXA scanning for PGC-1α+/+ and PGC-1α−/− mice (right graph). The results represent n = 4 (males) and n ≥ 11 (females) for each genotype at 24 wk. * p < 0.05 compared to corresponding PGC-1α+/+ mice.(B) The bars represent organ weights corrected to body weight for 3-wk-old male and female PGC-1α+/+ and PGC-1α−/− mice. The error bars represent ± SEM. Results represent n ≥ 14 for each group. * p < 0.05 compared to corresponding PGC-1α+/+ mice.
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pbio-0030101-g002: Evidence for Tissue-Specific Growth Abnormalities and Mild Sex-Limited, Age-Dependent Obesity in PGC-1α−/− Mice(A) The bars represent total body weight for the ages indicated for male (left graph) and female (center graph) PGC-1α+/+ and PGC-1α−/− mice. The body weight (BW) of the 1-wk-old PGC-1α−/− mice was normalized to that of PGC-1α+/+ littermates, which was assigned a value of 100 (left axis). For the 3-, 18-, and 24-wk time points, absolute weights of PGC-1α−/− mice were compared to age-matched controls (right axis). Percent fat as determined by DEXA scanning for PGC-1α+/+ and PGC-1α−/− mice (right graph). The results represent n = 4 (males) and n ≥ 11 (females) for each genotype at 24 wk. * p < 0.05 compared to corresponding PGC-1α+/+ mice.(B) The bars represent organ weights corrected to body weight for 3-wk-old male and female PGC-1α+/+ and PGC-1α−/− mice. The error bars represent ± SEM. Results represent n ≥ 14 for each group. * p < 0.05 compared to corresponding PGC-1α+/+ mice.

Mentions: Heterozygous (PGC-1α+/−) mice were bred to generate PGC-1α−/− offspring. The observed genotype ratios of the offspring were consistent with the expected Mendelian ratios (unpublished data). Unexpected deaths of the offspring were not observed, and PGC-1α+/− and PGC-1α−/− offspring appeared normal. Total body weights obtained 1 wk after birth revealed a 15%–20% reduction in total body mass for male and female PGC-1α−/− mice relative to sex-matched PGC-1α+/+ littermates (Figure 2). The weight decrement between PGC-1α−/− and PGC-1α+/+ littermates disappeared by 3 wk of age (Figure 2A). At 18 wk of age, body weight was modestly but significantly greater in male and female PGC-1α−/− mice compared to sex-matched PGC-1α+/+ controls (Figure 2A). This weight difference was also significant for female PGC-1α−/− mice at 24 wk of age (Figure 2A). The abnormal weight gain in PGC-1α−/− mice was not associated with differences in food intake (unpublished data) or alterations in general activity as monitored for 48 h (Figure S1). Percent body fat, as determined by dual-energy X-ray absorption (DEXA), was greater in 18- and 24-wk-old female PGC-1α−/− mice compared to age-matched female PGC-1α+/+ counterparts, indicating that the body weight difference was due, at least in part, to increased body fat (Figure 2A). Lean mass was not significantly different between the genotypes (unpublished data). Although DEXA did not detect excess body fat in male PGC-1α−/− mice at 18 or 24 wk of age, older male mutant mice (over 7 mo of age) accumulated more body fat than male WT controls (Figure 2A and 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)

Evidence for Tissue-Specific Growth Abnormalities and Mild Sex-Limited, Age-Dependent Obesity in PGC-1α−/− Mice(A) The bars represent total body weight for the ages indicated for male (left graph) and female (center graph) PGC-1α+/+ and PGC-1α−/− mice. The body weight (BW) of the 1-wk-old PGC-1α−/− mice was normalized to that of PGC-1α+/+ littermates, which was assigned a value of 100 (left axis). For the 3-, 18-, and 24-wk time points, absolute weights of PGC-1α−/− mice were compared to age-matched controls (right axis). Percent fat as determined by DEXA scanning for PGC-1α+/+ and PGC-1α−/− mice (right graph). The results represent n = 4 (males) and n ≥ 11 (females) for each genotype at 24 wk. * p < 0.05 compared to corresponding PGC-1α+/+ mice.(B) The bars represent organ weights corrected to body weight for 3-wk-old male and female PGC-1α+/+ and PGC-1α−/− mice. The error bars represent ± SEM. Results represent n ≥ 14 for each group. * p < 0.05 compared to corresponding PGC-1α+/+ mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1064854&req=5

pbio-0030101-g002: Evidence for Tissue-Specific Growth Abnormalities and Mild Sex-Limited, Age-Dependent Obesity in PGC-1α−/− Mice(A) The bars represent total body weight for the ages indicated for male (left graph) and female (center graph) PGC-1α+/+ and PGC-1α−/− mice. The body weight (BW) of the 1-wk-old PGC-1α−/− mice was normalized to that of PGC-1α+/+ littermates, which was assigned a value of 100 (left axis). For the 3-, 18-, and 24-wk time points, absolute weights of PGC-1α−/− mice were compared to age-matched controls (right axis). Percent fat as determined by DEXA scanning for PGC-1α+/+ and PGC-1α−/− mice (right graph). The results represent n = 4 (males) and n ≥ 11 (females) for each genotype at 24 wk. * p < 0.05 compared to corresponding PGC-1α+/+ mice.(B) The bars represent organ weights corrected to body weight for 3-wk-old male and female PGC-1α+/+ and PGC-1α−/− mice. The error bars represent ± SEM. Results represent n ≥ 14 for each group. * p < 0.05 compared to corresponding PGC-1α+/+ mice.
Mentions: Heterozygous (PGC-1α+/−) mice were bred to generate PGC-1α−/− offspring. The observed genotype ratios of the offspring were consistent with the expected Mendelian ratios (unpublished data). Unexpected deaths of the offspring were not observed, and PGC-1α+/− and PGC-1α−/− offspring appeared normal. Total body weights obtained 1 wk after birth revealed a 15%–20% reduction in total body mass for male and female PGC-1α−/− mice relative to sex-matched PGC-1α+/+ littermates (Figure 2). The weight decrement between PGC-1α−/− and PGC-1α+/+ littermates disappeared by 3 wk of age (Figure 2A). At 18 wk of age, body weight was modestly but significantly greater in male and female PGC-1α−/− mice compared to sex-matched PGC-1α+/+ controls (Figure 2A). This weight difference was also significant for female PGC-1α−/− mice at 24 wk of age (Figure 2A). The abnormal weight gain in PGC-1α−/− mice was not associated with differences in food intake (unpublished data) or alterations in general activity as monitored for 48 h (Figure S1). Percent body fat, as determined by dual-energy X-ray absorption (DEXA), was greater in 18- and 24-wk-old female PGC-1α−/− mice compared to age-matched female PGC-1α+/+ counterparts, indicating that the body weight difference was due, at least in part, to increased body fat (Figure 2A). Lean mass was not significantly different between the genotypes (unpublished data). Although DEXA did not detect excess body fat in male PGC-1α−/− mice at 18 or 24 wk of age, older male mutant mice (over 7 mo of age) accumulated more body fat than male WT controls (Figure 2A and 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