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Endocrinol Metab Clin N Am 37 (2008) 635–646

Obesity and Free Fatty Acids
Guenther Boden, MD
Department of Medicine, Division of Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA 19140, USA

Obesity is closely associated with insulin resistance (peripheral and hepatic) [1] and with a low-gradestate of inflammation characterized by the elevation of proinflammatory cytokines in blood and tissues [2]. Insulin and inflammation contribute to the development of type 2 diabetes mellitus (T2DM), hypertension, atherogenic dyslipidemias, and disorders of blood coagulation and fibrinolysis. All of these disorders are independent risk factors for atherosclerotic vascular disease (ASVD) such as heartattacks, strokes, and peripheral arterial disease [3]. The reason why obesity is associated with insulin resistance is not well understood. This article reviews the evidence demonstrating that free fatty acids (FFAs) cause insulin resistance and inflammation in the major insulin target tissues (skeletal muscle, liver, and endothelial cells) and thus are an important link between obesity, insulinresistance, inflammation, and the development of T2DM, hypertension, dyslipidemia, disorders of coagulation, and ASVD (Fig. 1). The central nervous system effects of FFAs, including the demonstration that infusion of oleic acid into the third ventricle of rats reduced food intake and hepatic glucose production (HGP), are reviewed separately elsewhere in this issue.

Free fatty acids and insulinresistance 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

This work was supported by National Institutes of Health grants RO1-DK-68895, RO1-HL-733267, and RO1-DK-066003. E-mail address: bodengh@tuhs.temple.edu 0889-8529/08/$ - see frontmatter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2008.06.007 endo.theclinics.com

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BODEN

OBESITY

INSULIN RESISTANCE

INFLAMMATION

T2DM

HYPERTENSION

DYSLIPIDEMIA

COAG/FIBRIN

ASVD

Fig. 1. Relationship between obesity, insulin resistance, inflammation, and ASVD. Obesity causes insulin resistance and a state of low-grade inflammation. Both conditionscontribute to the development of several disorders, including T2DM, hypertension, dyslipidemia, and disorders of coagulation and fibrinolysis, which are independent risk factors for the development of ASVD.

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 a (TNF-a), interleukin (IL)-6, IL-1b, and others. Some of these compounds, when infused in large amounts, can produce insulin resistance; however, any substance, to qualify as a physiologic link between obesity and insulin resistance, should meet at least the following three criteria: (1) the substance should be elevated in the blood of obese people; (2) raising its bloodlevel (within physiologic limits) should increase insulin resistance; and (3) lowering its blood level should decrease insulin resistance. So far, only FFAs meet these three criteria in human subjects. Plasma FFA levels are elevated in most obese individuals [5]; raising plasma FFA levels increases insulin resistance [6] and lowering FFA levels improves insulin resistance [7]. Free fatty acidlevels are elevated in obesity Plasma FFA levels are usually elevated in obesity because (1) the enlarged adipose tissue mass releases more FFAs and (2) FFA clearance may be reduced [8]. Moreover, after plasma FFA levels are elevated, they will inhibit insulin’s antilipolytic action, which will further increase the rate of FFA release into the circulation [9]. Raising free fatty acid levels...