title: Thrombospondin 1 mediates high-fat diet-induced muscle fibrosis and insulin resistance in male mice.
abstract: Thrombospondin 1 (THBS1 or TSP-1) is a circulating glycoprotein highly expressed in hypertrophic visceral adipose tissues of humans and mice. High-fat diet (HFD) feeding induces the robust increase of circulating THBS1 in the early stages of HFD challenge. The loss of Thbs1 protects male mice from diet-induced weight gain and adipocyte hypertrophy. Hyperinsulinemic euglycemic clamp study has demonstrated that Thbs1-null mice are protected from HFD-induced insulin resistance. Tissue-specific glucose uptake study has revealed that the insulin-sensitive phenotype of Thbs1-null mice is mostly mediated by skeletal muscles. Further assessments of the muscle phenotype using RNA sequencing, quantitative PCR, and histological studies have demonstrated that Thbs1-null skeletal muscles are protected from the HFD-dependent induction of Col3a1 and Col6a1, coupled with a new collagen deposition. At the same time, the Thbs1-null mice display a better circadian rhythm and higher amplitude of energy expenditure with a browning phenotype in sc adipose tissues. These results suggest that THBS1, which circulates in response to a HFD, may induce insulin resistance and fibrotic tissue damage in skeletal muscles as well as the de-browning of sc adipose tissues in the early stages of a HFD challenge. Our study may shed new light on the pathogenic role played by a circulating extracellular matrix protein in the cross talk between adipose tissues and skeletal muscles during obesity progression.
authors.affiliation: MD, PhD, or Mayumi Inoue, MD, PhD, University of Michigan, NCRC B10-A186, 2800 Plymouth Road, Ann Arbor, MI 48109-2800. taehwa@umich.edu; or mayu@umich.edu.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Inoue
authors.forename: Yibin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Richard H
authors.initials: RH
authors.lastname: Barnes
authors.forename: Masakuni
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martinez-Santibañez
authors.forename: Lynn
authors.initials: L
authors.lastname: Geletka
authors.forename: Carey N
authors.initials: CN
authors.lastname: Lumeng
authors.forename: David A
authors.initials: DA
authors.lastname: Buchner
authors.forename: Tae-Hwa
authors.initials: TH
authors.lastname: Chun
mesh_terms: D041721:3T3-L1 Cells; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004822:Epididymis; D005355:Fibrosis / Q000139:chemically induced*; D005786:Gene Expression Regulation / Q000187:drug effects; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000209:etiology*; D009765:Obesity; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D004041:Dietary Fats; D019700:Thrombospondin 1