title: Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance.
abstract: PGC-1beta is a transcriptional coactivator that potently stimulates mitochondrial biogenesis and respiration of cells. Here, we have generated mice lacking exons 3 to 4 of the Pgc-1beta gene (Pgc-1beta(E3,4-/E3,4-) mice). These mice express a mutant protein that has reduced coactivation activity on a subset of transcription factors, including ERRalpha, a major target of PGC-1beta in the induction of mitochondrial gene expression. The mutant mice have reduced expression of OXPHOS genes and mitochondrial dysfunction in liver and skeletal muscle as well as elevated liver triglycerides. Euglycemic-hyperinsulinemic clamp and insulin signaling studies show that PGC-1beta mutant mice have normal skeletal muscle response to insulin but have hepatic insulin resistance. These results demonstrate that PGC-1beta is required for normal expression of OXPHOS genes and mitochondrial function in liver and skeletal muscle. Importantly, these abnormalities do not cause insulin resistance in skeletal muscle but cause substantially reduced insulin action in the liver.
authors.affiliation: Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Vianna
authors.forename: Michael
authors.initials: M
authors.lastname: Huntgeburth
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppari
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Jiandie
authors.initials: J
authors.lastname: Lin
authors.forename: Stefan
authors.initials: S
authors.lastname: Krauss
authors.forename: Giorgio
authors.initials: G
authors.lastname: Barbatelli
authors.forename: Iphigenia
authors.initials: I
authors.lastname: Tzameli
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009928:Organ Specificity; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse