Thrombospondin 1 Mediates High-Fat Diet-Induced Muscle Fibrosis and Insulin Resistance in Male Mice
Open accessAbstract
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.
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ECM remodeling causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.
“ECM remodeling170, 172, 173, 178 causes changes in signaling via cell surface receptors that sense the extracellular microenvironment.162, 179-181”
From The Vasculature in Prediabetes (2018) · cites this paper as [170]
Thrombospondin-1 contributes to the skeletal muscle meta-fibrosis and insulin resistance in high fat-fed mice.
“Thrombospondin-1 contributes to the skeletal muscle meta-fibrosis and insulin resistance in high fat-fed mice.”
From The Vasculature in Prediabetes (2018) · cites this paper as [170]
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- Authors
- Inoue, M., Jiang, Y., Barnes, R. H., Tokunaga, M., Martinez-Santibañez, G., Geletka, L., Lumeng, C. N., Buchner, D. A., & Chun, T.-H.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Inoue, Mayumi
- Chun, Tae-Hwa
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2013-12-01
- Volume
- 154
- Issue
- 12
- Pages
- 4548-4559
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3836064
- OpenAlex
- W2042787985
- Cited by
- 85
- References
- 51
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 15 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 8 · 2016: 9 · 2015: 9 · 2014: 2
- FWCI
- 4.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Vanderbilt University (DK059637)
- University of Michigan (48109, T32 GM007315, DK089503, DK020572)
- National Children's Research Centre
- National Institutes of Health (DK,059637, DK020572, DK089503)
- College of Pharmacy, University of Michigan
- National Heart, Lung, and Blood Institute (R21HL106332, HL106332)
- National Institute of General Medical Sciences (T32GM007315)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK020572, P60DK020572, DK089503, R01DK090262, U24DK059637, DK 059637, DK095137, DK090262, K01DK084079, DK084079, R01DK095137, P30DK092926, P30DK020572, P30DK089503)
- Michigan Nutrition Obesity Research Center, Medical School, University of Michigan
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- thrombospondin-1, high-fat diet, muscle fibrosis, insulin resistance, skeletal muscle, visceral adipose tissue, adipocyte hypertrophy, collagen deposition, circadian rhythm, energy expenditure, brown adipose tissue, obesity, extracellular matrix proteins
- MeSH terms
- Animals, Dietary Fats, Dose-Response Relationship, Drug, Epididymis, Fibrosis, Gene Expression Regulation, Insulin Resistance, Male, Mice, Inbred C57BL, Muscular Diseases, Obesity, Glucose Clamp Technique, Mice, Knockout, Muscle, Skeletal, Thrombospondin 1, 3T3-L1 Cells, Mice, Adipose Tissue, White, Transcriptome
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