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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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Female PGC-1α−/− Mice Are More Glucose Tolerant and Insulin Sensitive Compared to PGC-1α+/+ on High-Fat Diet(A) At 4.5 mo of age, glucose tolerance testing (GTT) was performed on female PGC-1α+/+ (n = 6) and PGC-1α−/− (n = 6) mice maintained on standard chow.(B) At 8 wk of age, PGC-1α+/+ (n = 8) and PGC-1α−/− (n = 11) mice were provided a diet containing 43% of its calories from fat (HF chow). The graphs depict blood glucose levels ± SEM in PGC-1α−/− mice during GTT (left graph) and ITT (right graph) studies. Studies were performed 5 wk (GTT) and 6 wk (ITT) after the initiation of the high-fat diet. * p < 0.05 compared to PGC-1α+/+ mice at the same time point.
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pbio-0030101-g009: Female PGC-1α−/− Mice Are More Glucose Tolerant and Insulin Sensitive Compared to PGC-1α+/+ on High-Fat Diet(A) At 4.5 mo of age, glucose tolerance testing (GTT) was performed on female PGC-1α+/+ (n = 6) and PGC-1α−/− (n = 6) mice maintained on standard chow.(B) At 8 wk of age, PGC-1α+/+ (n = 8) and PGC-1α−/− (n = 11) mice were provided a diet containing 43% of its calories from fat (HF chow). The graphs depict blood glucose levels ± SEM in PGC-1α−/− mice during GTT (left graph) and ITT (right graph) studies. Studies were performed 5 wk (GTT) and 6 wk (ITT) after the initiation of the high-fat diet. * p < 0.05 compared to PGC-1α+/+ mice at the same time point.

Mentions: Recent studies have suggested that specific PGC-1α single nucleotide polymorphisms and haplotypes may influence the development of insulin resistance and diabetes [27,30] and that PGC-1 activity is diminished in insulin-resistant and diabetic muscle [22,23]. Accordingly, peripheral glucose disposal and insulin responsiveness were examined in PGC-1α−/− mice. Glucose tolerance testing of 2-mo-old male and female mice revealed no significant difference in blood glucose excursion between PGC-1α+/+ and PGC-1α−/− groups (unpublished data). Given that older female PGC-1α−/− mice develop an increase in body fat stores, glucose tolerance and insulin responsiveness were further evaluated in this group. Glucose tolerance testing in 4.5-mo-old female PGC-1α−/− mice revealed that, despite increased body weight [mean ± standard error of the mean (SEM) weight of PGC-1α+/+ mice = 22.4 ± 0.79 g; PGC-1α−/− mice = 25.2 ± 1.04 g), PGC-1α−/− mice exhibited similar levels of glucose tolerance compared to WT mice on standard rodent chow (Figure 9). To examine glucose homeostasis in response to high-fat diet, female PGC-1α+/+ and PGC-1α−/− mice were placed on high-fat chow (43% calories from fat) for 6 wk starting at 8 wk of age. The weight gained on the high-fat diet was similar for the PGC-1α+/+ and PGC-1α−/− groups (Figure S3). Surprisingly, the PGC-1α−/− mice on a high-fat diet were significantly more glucose-tolerant and insulin-sensitive compared to the PGC-1α+/+ mice (Figure 9B). Taken together, these results indicate that, despite excess body fat under standard conditions, the female PGC-1α−/− mice do not exhibit insulin resistance. Moreover, the PGC-1α−/− mice are more glucose-tolerant and insulin-sensitive than WT mice on a high-fat diet.


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)

Female PGC-1α−/− Mice Are More Glucose Tolerant and Insulin Sensitive Compared to PGC-1α+/+ on High-Fat Diet(A) At 4.5 mo of age, glucose tolerance testing (GTT) was performed on female PGC-1α+/+ (n = 6) and PGC-1α−/− (n = 6) mice maintained on standard chow.(B) At 8 wk of age, PGC-1α+/+ (n = 8) and PGC-1α−/− (n = 11) mice were provided a diet containing 43% of its calories from fat (HF chow). The graphs depict blood glucose levels ± SEM in PGC-1α−/− mice during GTT (left graph) and ITT (right graph) studies. Studies were performed 5 wk (GTT) and 6 wk (ITT) after the initiation of the high-fat diet. * p < 0.05 compared to PGC-1α+/+ mice at the same time point.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1064854&req=5

pbio-0030101-g009: Female PGC-1α−/− Mice Are More Glucose Tolerant and Insulin Sensitive Compared to PGC-1α+/+ on High-Fat Diet(A) At 4.5 mo of age, glucose tolerance testing (GTT) was performed on female PGC-1α+/+ (n = 6) and PGC-1α−/− (n = 6) mice maintained on standard chow.(B) At 8 wk of age, PGC-1α+/+ (n = 8) and PGC-1α−/− (n = 11) mice were provided a diet containing 43% of its calories from fat (HF chow). The graphs depict blood glucose levels ± SEM in PGC-1α−/− mice during GTT (left graph) and ITT (right graph) studies. Studies were performed 5 wk (GTT) and 6 wk (ITT) after the initiation of the high-fat diet. * p < 0.05 compared to PGC-1α+/+ mice at the same time point.
Mentions: Recent studies have suggested that specific PGC-1α single nucleotide polymorphisms and haplotypes may influence the development of insulin resistance and diabetes [27,30] and that PGC-1 activity is diminished in insulin-resistant and diabetic muscle [22,23]. Accordingly, peripheral glucose disposal and insulin responsiveness were examined in PGC-1α−/− mice. Glucose tolerance testing of 2-mo-old male and female mice revealed no significant difference in blood glucose excursion between PGC-1α+/+ and PGC-1α−/− groups (unpublished data). Given that older female PGC-1α−/− mice develop an increase in body fat stores, glucose tolerance and insulin responsiveness were further evaluated in this group. Glucose tolerance testing in 4.5-mo-old female PGC-1α−/− mice revealed that, despite increased body weight [mean ± standard error of the mean (SEM) weight of PGC-1α+/+ mice = 22.4 ± 0.79 g; PGC-1α−/− mice = 25.2 ± 1.04 g), PGC-1α−/− mice exhibited similar levels of glucose tolerance compared to WT mice on standard rodent chow (Figure 9). To examine glucose homeostasis in response to high-fat diet, female PGC-1α+/+ and PGC-1α−/− mice were placed on high-fat chow (43% calories from fat) for 6 wk starting at 8 wk of age. The weight gained on the high-fat diet was similar for the PGC-1α+/+ and PGC-1α−/− groups (Figure S3). Surprisingly, the PGC-1α−/− mice on a high-fat diet were significantly more glucose-tolerant and insulin-sensitive compared to the PGC-1α+/+ mice (Figure 9B). Taken together, these results indicate that, despite excess body fat under standard conditions, the female PGC-1α−/− mice do not exhibit insulin resistance. Moreover, the PGC-1α−/− mice are more glucose-tolerant and insulin-sensitive than WT mice on a high-fat diet.

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