Endocrinology and Metabolism Clinics of North America
Obesity and Free Fatty Acids
Section snippets
Free fatty acids and insulin resistance
The recognition that adipose tissue not only stores and releases fatty acids but also synthesizes and releases a large number of other active compounds [4] has provided a conceptual framework that helps to understand how obesity can result in the development of insulin resistance. According to this concept, an expanding fat mass releases increasing amounts of compounds such as FFAs, angiotensin 2, resistin, tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β, and others. Some of these
Free fatty acids and inflammation
Obesity is associated with elevated levels of proinflammatory cytokines and chemokines in the circulation and in tissues [2]. As mentioned earlier, adipose tissue produces and releases a large number of cytokines and chemokines (collectively called adipokines) [4], some of which are proinflammatory. Recent studies have shed some light on the reasons for the increased release of proinflammatory cytokines in obesity. In one study, mice fed a high-fat diet for 3 months developed low-grade hepatic
Free fatty acids and the metabolic syndrome
The increase in the metabolic syndrome (also called the insulin-resistance syndrome) is mainly driven by the worldwide increase in obesity. Not surprisingly, therefore, obesity-associated and fatty acid–mediated insulin resistance is intimately connected with all major components of this syndrome; that is, T2DM, hypertension, atherogenic dyslipidemia, and other components that have not yet been formally included in the metabolic syndrome complex such as disorders of blood coagulation and
Free fatty acids and matrix metalloproteinases
Smoking, together with the established insulin resistance–related risk factors for ASVD such as T2DM, hypertension, atherogenic dyslipidemia, and disorders of blood coagulation and fibrinolysis, probably cannot completely explain the obesity/insulin resistance–related ASVD risk [48]. This suggests that there may be other ways by which insulin resistance can increase this risk. Indeed, one such risk factor may be increased activity of several matrix metalloproteinases (MMPs). MMPs are enzymes
Free fatty acids as target for therapy
Because insulin resistance is at the core of several serious health problems associated with obesity, insulin resistance should be a major focus of therapy. Whereas weight loss through diet and exercise is clearly the most desirable way to reduce insulin resistance in obese people, diet and exercise programs and presently available pharmacologic approaches have not been very successful. As noted earlier, elevated plasma FFA levels are responsible for much of the insulin resistance in obese
Summary
Plasma FFA levels are elevated in obesity. FFAs cause insulin resistance in all major insulin target organs (skeletal muscle, liver, endothelial cells) and have emerged as a major link between obesity, the development of the metabolic syndrome, and ASVD. Mechanisms through which FFAs induce insulin resistance involve intramyocellular and intrahepatic accumulation of DAG and triglycerides, activation of several serine/threonine kinases, reduction of tyrosine phosphorylation of the IRS 1/2, and
Acknowledgments
The author thanks Maria Mozzoli, BS, and Karen Kresge, BS, for technical assistance, and Constance Harris Crews for typing the manuscript.
References (60)
Insulin resistance and vascular function
J Diabet Complications
(2002)- et al.
Mechanism by which fatty acids inhibit activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle
J Biol Chem
(2002) - et al.
Regulation of Glut4 gene expression by arachidonic acid. Evidence for multiple pathways, one of which requires oxidation to prostaglandin
European Journal of Biological Chemistry
(1996) - et al.
Free fatty acids repress the Glut4 gene expression in cardiac muscle via novel response elements
J Biol Chem
(2005) - et al.
Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human monocytes
Blood
(1991) - et al.
Obesity and atherogenic dyslipidemia
Gastroenterology
(2007) - et al.
Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects
Metabolism
(1986) - et al.
Platelet function, coagulopathy, and impaired fibrinolysis in diabetes
Cardiol Clin
(2004) - et al.
Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteinases 1, 2 and 9 in the human coronary artery
Atherosclerosis
(2000) Role of fatty acids in the pathogenesis of insulin resistance and NIDDM
Diabetes
(1997)
Burning question. Does an adipokines-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes?
Diabetes
Medical consequences of obesity
J Clin Endocrinol Metab
Adipose tissue as an endocrine organ
J Clin Endocrinol Metab
Measurement of plasma glucose, free fatty acid, lactate and insulin for 24 h in patients with NIDDM
Diabetes
Mechanisms of fatty acid-induced inhibition of glucose uptake
J Clin Invest
Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects
Diabetes
Plasma free fatty acid turnover in obesity
Acta Med Scand
Influence of body fat distribution on free fatty acid metabolism in obesity
J Clin Invest
Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes
J Clin Invest
Effects of fat on insulin stimulated carbohydrate metabolism in normal men
J Clin Invest
Dose-response characteristics for effects of insulin on production and utilization of glucose in man
Am J Phys
FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis
Am J Phys
Roles for insulin receptor, PI3-kinase and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells
Circulation
Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation
J Clin Invest
Effect on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes
Am J Physiol Endocrinol Metab
Effects of free fatty acids on glucose transport and IRS-1 associated phosphatidylinositol 3-kinase activity
J Clin Invest
Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects
Diabetes
Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α
Diabetes
Diabetes mellitus: a fundamental and clinical text
Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver
Diabetes
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This work was supported by National Institutes of Health grants RO1-DK-68895, RO1-HL-733267, and RO1-DK-066003.