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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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Fasting-Induced Hepatic Steatosis Develops in PGC-1α−/− Mice(A) The photograph depicts the development of a pale liver in PGC-1α−/− mice subjected to a 24-h fast.(B) Oil red O staining of histologic sections of liver taken from PGC-1α−/− mice under fed and 24 h fasted conditions. The red staining indicates neutral lipid.(C) Representative electron micrographs of the liver from PGC-1α+/+ and PGC-1α−/− mice following a 24-h fast. The droplets are indicative of neutral lipid accumulation.(D) Mean liver TAG levels in PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) mice under fed and 24-h fasted conditions. * p < 0.05.
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pbio-0030101-g007: Fasting-Induced Hepatic Steatosis Develops in PGC-1α−/− Mice(A) The photograph depicts the development of a pale liver in PGC-1α−/− mice subjected to a 24-h fast.(B) Oil red O staining of histologic sections of liver taken from PGC-1α−/− mice under fed and 24 h fasted conditions. The red staining indicates neutral lipid.(C) Representative electron micrographs of the liver from PGC-1α+/+ and PGC-1α−/− mice following a 24-h fast. The droplets are indicative of neutral lipid accumulation.(D) Mean liver TAG levels in PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) mice under fed and 24-h fasted conditions. * p < 0.05.

Mentions: Previous studies have implicated PGC-1α in several hepatic metabolic functions including fatty acid oxidation and gluconeogenesis [18,19,20,21]. Accordingly, the hepatic phenotype was evaluated under basal conditions and following a 24-h fast, a stimulus known to induce fatty acid oxidation and gluconeogenic rates in liver. Under basal fed conditions, the livers of the PGC-1α−/− mice appeared grossly normal and did not exhibit histologic abnormalities (unpublished data). However, following a 24 h-fast, the PGC-1α−/− mice exhibited marked hepatic steatosis as determined by gross inspection, oil red O staining, electron microscopy, and measurements of liver triglyceride (TAG) levels (Figure 7). There were no differences in plasma triglycerides or free fatty acids between the genotypes in fed or fasted states (unpublished data). To further investigate the mechanisms involved in the fasting-induced hepatic steatotic response, hepatocytes were isolated from PGC-1α−/− mice and WT controls. Oleate loading experiments revealed that the PGC-1α−/− hepatocytes accumulated neutral lipid to a significantly greater extent than the WT cells (Figure 8A). 3H-palmitate oxidation rates were significantly lower in PGC-1α−/− hepatocytes compared to PGC-1α+/+ hepatocytes under basal conditions and following exposure to oleate (Figure 8B). Taken together, these latter results indicate a cell-autonomous defect in PGC-1α−/− hepatocytes that results in an inability to maintain cellular lipid balance in the context of increased delivery of lipid such as occurs with fasting.


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)

Fasting-Induced Hepatic Steatosis Develops in PGC-1α−/− Mice(A) The photograph depicts the development of a pale liver in PGC-1α−/− mice subjected to a 24-h fast.(B) Oil red O staining of histologic sections of liver taken from PGC-1α−/− mice under fed and 24 h fasted conditions. The red staining indicates neutral lipid.(C) Representative electron micrographs of the liver from PGC-1α+/+ and PGC-1α−/− mice following a 24-h fast. The droplets are indicative of neutral lipid accumulation.(D) Mean liver TAG levels in PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) mice under fed and 24-h fasted conditions. * p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064854&req=5

pbio-0030101-g007: Fasting-Induced Hepatic Steatosis Develops in PGC-1α−/− Mice(A) The photograph depicts the development of a pale liver in PGC-1α−/− mice subjected to a 24-h fast.(B) Oil red O staining of histologic sections of liver taken from PGC-1α−/− mice under fed and 24 h fasted conditions. The red staining indicates neutral lipid.(C) Representative electron micrographs of the liver from PGC-1α+/+ and PGC-1α−/− mice following a 24-h fast. The droplets are indicative of neutral lipid accumulation.(D) Mean liver TAG levels in PGC-1α+/+ (n = 5) and PGC-1α−/− (n = 5) mice under fed and 24-h fasted conditions. * p < 0.05.
Mentions: Previous studies have implicated PGC-1α in several hepatic metabolic functions including fatty acid oxidation and gluconeogenesis [18,19,20,21]. Accordingly, the hepatic phenotype was evaluated under basal conditions and following a 24-h fast, a stimulus known to induce fatty acid oxidation and gluconeogenic rates in liver. Under basal fed conditions, the livers of the PGC-1α−/− mice appeared grossly normal and did not exhibit histologic abnormalities (unpublished data). However, following a 24 h-fast, the PGC-1α−/− mice exhibited marked hepatic steatosis as determined by gross inspection, oil red O staining, electron microscopy, and measurements of liver triglyceride (TAG) levels (Figure 7). There were no differences in plasma triglycerides or free fatty acids between the genotypes in fed or fasted states (unpublished data). To further investigate the mechanisms involved in the fasting-induced hepatic steatotic response, hepatocytes were isolated from PGC-1α−/− mice and WT controls. Oleate loading experiments revealed that the PGC-1α−/− hepatocytes accumulated neutral lipid to a significantly greater extent than the WT cells (Figure 8A). 3H-palmitate oxidation rates were significantly lower in PGC-1α−/− hepatocytes compared to PGC-1α+/+ hepatocytes under basal conditions and following exposure to oleate (Figure 8B). Taken together, these latter results indicate a cell-autonomous defect in PGC-1α−/− hepatocytes that results in an inability to maintain cellular lipid balance in the context of increased delivery of lipid such as occurs with fasting.

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