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TNF- downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents
Open accessAbstract
Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-alpha. Our findings demonstrate that TNF-alpha impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.
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“lower NOS3 abundance is found in both adipose tissue and skeletal muscle of obese humans and rodents [120-124].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [123]
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“was shown to downregulate NOS3 expression and abundance [123, 131-134] by decreasing the stability of NOS3 mRNA [135, 136], effectively shortening its half-life [137].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [123]
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Metadata
- Authors
- Valerio, A.
- Affiliations
- University of Milan (IT)
- Corresponding author
- Valerio, A.
- ORCID
- Valerio, A.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-10-02
- Volume
- 116
- Issue
- 10
- Pages
- 2791-2798
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2147649093
- Cited by
- 327
- References
- 56
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 5 · 2023: 14 · 2022: 10 · 2021: 7 · 2020: 12 · 2019: 14 · 2018: 15 · 2017: 19 · 2016: 14 · 2015: 19 · 2014: 24 · 2013: 16 · 2012: 27
- FWCI
- 14.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- TNF-α, endothelial nitric oxide synthase, mitochondrial biogenesis, obesity, adipose tissue, brown adipose tissue, white adipose tissue, skeletal muscle, TNF receptor 1, low-grade inflammation, nitric oxide, satellite cells, adipocytes, weight gain
- MeSH terms
- Adenosine Triphosphate, Adipose Tissue, Animals, Cells, Cultured, Electron Transport Complex IV, DNA-Binding Proteins, Female, High Mobility Group Proteins, Male, Mice, Inbred C57BL, Mice, Obese, Mitochondria, Obesity, Oxygen Consumption, Rats, Zucker, Tumor Necrosis Factor-alpha, Down-Regulation, Receptors, Tumor Necrosis Factor, Mice, Knockout, Muscle, Skeletal, Nitric Oxide Donors, Cytochromes c, Nuclear Respiratory Factor 1, Mice, Rats, Nitric Oxide Synthase Type III
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