Cited by 819Adipokines, Inflammation, and Metabolic DiseasesMetabolism, Diabetes, and CancerAdipose Tissue and Metabolism

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Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha.

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Hotamisligil, G S, Budavari, A, Murray, D, Spiegelman, B M·1994·Journal of Clinical Investigation

DOI 10.1172/jci117495PMC PMC295304

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Abstract

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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Authors: Hotamisligil, G. S., Budavari, A., Murray, D., & Spiegelman, B. M.
Affiliations: Harvard University (US)
ORCID: Spiegelman, B M
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1994-10-01
Volume: 94
Issue: 4
Pages: 1543-1549
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci117495
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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Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha.

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