Free Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor-κB Pathway in Rat Liver
Abstract
To study mechanisms by which free fatty acids (FFAs) cause hepatic insulin resistance, we have used euglycemic-hyperinsulinemic clamping with and without infusion of lipid/heparin (to raise or to lower plasma FFAs) in alert male rats. FFA-induced hepatic insulin resistance was associated with increased hepatic diacylglycerol content (+210%), increased activities of two serine/threonine kinases (protein kinase C-delta and inhibitor of kappaB [IkappaB] kinase-beta), increased activation of the proinflammatory nuclear factor-kappaB (NF-kappaB) pathway (IkappaB kinase-beta, +640%; IkappaB-alpha, -54%; and NF-kappaB, +73%), and increased expression of inflammatory cytokines (tumor necrosis factor-alpha, +1,700% and interleukin-1beta, +440%) and plasma levels of monocyte chemoattractant protein-1 (+220%). We conclude that FFAs caused hepatic insulin resistance, which can produce overproduction of glucose and hyperglycemia, and initiated inflammatory processes in the liver that could potentially result in the development of steatohepatitis.
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The development of hepatic insulin resistance after lipid infusions was associated with activation of the Iκ kinase β-nuclear factor-κB pathway.
“The development of hepatic insulin resistance after lipid infusions was associated with activation of the Iκ kinase β-nuclear factor-κB pathway.125”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [125]
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- Authors
- Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., Xiang, X., Luo, Z., & Ruderman, N.
- Affiliations
- Temple University (US)
- Boston University (US)
- ORCID
- Ruderman, Neil
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-12-01
- Volume
- 54
- Issue
- 12
- Pages
- 3458-3465
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2152527784
- Cited by
- 528
- References
- 40
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 17 · 2023: 24 · 2022: 15 · 2021: 23 · 2020: 26 · 2019: 18 · 2018: 24 · 2017: 16 · 2016: 27 · 2015: 37 · 2014: 26 · 2013: 38 · 2012: 28
- FWCI
- 21.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Institute on Aging (R01 AG 15353)
- National Heart, Lung, and Blood Institute (R01 HL 733267)
- National Institute on Drug Abuse (P30DA013429)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK066003, R01DK058895)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- free fatty acids, hepatic insulin resistance, NF-κB signaling, diacylglycerol, protein kinase C delta, IκB kinase β, IκBα, TNF-α, IL-1β, MCP-1, liver inflammation, steatohepatitis, hyperglycemia
- MeSH terms
- NF-KappaB Inhibitor alpha, Adenylate Kinase, Animals, Blood Glucose, Fatty Acids, Nonesterified, Insulin, Insulin Resistance, Kinetics, Liver, Male, Protein Kinase C, Glucose Clamp Technique, NF-kappa B, Rats, Sprague-Dawley, I-kappa B Proteins, Rats
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