Free Fatty Acids, A Major Link Between Obesity, Insulin Resistance, Inflammation, and Atherosclerotic Vascular Disease

Abstract

Plasma free fatty acids (FFAs) are elevated in obesity. By causing insulin resistance in all major insulin targets including muscle, liver, and endothelial cells, FFAs contribute to the development of type 2 diabetes (T2DM), hypertension, dyslipidemia, disorders of blood coagulation and fibrinolysis, and nonalcoholic fatty liver disease (NAFLD). In pancreatic β-cells, FFAs potentiate glucose-stimulated insulin secretion precisely to the extent needed to compensate for the FFA-induced insulin resistance. This prevents T2DM in the majority of obese, insulin-resistant individuals. On the other hand, in people with inherited defects of β-cell function (pre-diabetics), this compensation fails and T2DM develops. The mechanism through which FFA induces insulin resistance is postulated to involve intracellular accumulation of triglycerides and diacylglycerol, activation of several serine/threonine kinases, resulting in reduction of tyrosine phosphorylation of the insulin receptor substrate (IRS) 1/2 and impairment of the IRS/phosphoinositol 3 kinase pathway of insulin signaling. Elevated plasma FFA levels also produce low-grade inflammation in skeletal muscle and liver via activation of the nuclear factor κB pathway which results in synthesis and release of proinflammatory and proatherogenic cytokines. Thus, elevated FFA levels, present in obese people or due to high fat feeding, cause insulin resistance in all major insulin targets and are a major cause for the development of T2DM. In addition, FFAs produce a state of low-grade inflammation, and increase hepatic production of very low density lipoprotein (VLDL), and via producing insulin resistance and hyperinsulinemia promote a state of increased blood coagulation and decreased fibrinolysis. All these effects contribute to the development of atherosclerotic vascular disease and NAFLD.