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Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha.
Open accessAbstract
Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
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“Several animal models of obesity and insulin resistance show significantly higher levels of TNF␣ mRNA and protein compared with their lean counterparts (47-49)”
From Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [47]
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Flagged first, then by citations
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Self-citationMechanisms of Insulin Action and Insulin Resistance
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15-Deoxy-Δ12,14-Prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ
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Self-citation
Metadata
- Authors
- Hotamisligil, G. S., Budavari, A., Murray, D., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- ORCID
- Spiegelman, B M
- Venue
- Journal of Clinical Investigation
- Published
- 1994-10-01
- Volume
- 94
- Issue
- 4
- Pages
- 1543-1549
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC295304
- OpenAlex
- W2053200285
- Cited by
- 819
- References
- 29
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 14 · 2023: 13 · 2022: 23 · 2021: 22 · 2020: 26 · 2019: 15 · 2018: 26 · 2017: 20 · 2016: 25 · 2015: 31 · 2014: 24 · 2013: 39 · 2012: 30
- FWCI
- 21.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Joslin Diabetes Center
- National Institutes of Health (5r01dk042539-08)
- Genentech
- National Institute of Diabetes and Digestive and Kidney Diseases (DK42539)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- insulin receptor tyrosine kinase, insulin resistance, TNF-α, obesity, type 2 diabetes, IRS-1, soluble TNF receptors, adipose tissue, skeletal muscle, adipocytes, glucose uptake, free fatty acids, plasma glucose, insulin, Zucker fatty rats
- MeSH terms
- Adipose Tissue, Animals, Diabetes Mellitus, Diabetes Mellitus, Type 2, Disease Models, Animal, Immunoglobulin G, Insulin, Insulin Resistance, Liver, Male, Muscles, Neutralization Tests, Obesity, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Rats, Zucker, Receptor, Insulin, Recombinant Fusion Proteins, Specific Pathogen-Free Organisms, Tumor Necrosis Factor-alpha, Tyrosine, Receptors, Tumor Necrosis Factor, Phosphotyrosine, Rats, Insulin Receptor Substrate Proteins
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