title: PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.
abstract: The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (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.
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: John J
authors.initials: JJ
authors.lastname: Lehman
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Schaeffer
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Michael
authors.initials: M
authors.lastname: Courtois
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.forename: Nandakumar
authors.initials: N
authors.lastname: Sambandam
authors.forename: Carlos
authors.initials: C
authors.lastname: Bernal-Mizrachi
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.forename: John O
authors.initials: JO
authors.lastname: Holloszy
authors.forename: Denis M
authors.initials: DM
authors.lastname: Medeiros
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D002561:Cerebrovascular Disorders / Q000235:genetics; D005091:Exons; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics*; D005260:Female; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics*; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors