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 TNFα mRNA and protein compared with their lean counterparts.
“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 <i>Mfn2</i>, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [47]
The Results section says lean Zucker rats do not overexpress TNFα and that obese rats produce it in excess, supporting an obese–lean difference in one animal model. The Discussion also refers to increased TNFα production from fat cells in obesity. Our copy does not establish significantly higher TNFα mRNA and protein levels across several animal models. (LLM, conf=0.82)
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- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › 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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