title: Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk.
abstract: The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1alpha and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1alpha expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1alpha knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic beta cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1alpha in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Sherry
authors.initials: S
authors.lastname: Chin
authors.forename: Sheene
authors.initials: S
authors.lastname: Kim
authors.forename: Dan
authors.initials: D
authors.lastname: Kawamori
authors.forename: Amarnath J
authors.initials: AJ
authors.lastname: Kurpad
authors.forename: Nicole
authors.initials: N
authors.lastname: Neubauer
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight; D002450:Cell Communication / Q000502:physiology*; D005215:Fasting; D005260:Female; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D015415:Biomarkers; D007328:Insulin; D015850:Interleukin-6; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D005947:Glucose