Obesity and free fatty acids

Abstract

Plasma free fatty acid (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 atherosclerotic vascular disease. FFAs also produce low-grade inflammation in skeletal muscle, liver, and fat, which may contribute to cardiovascular events. The challenges for the future include the prevention or correction of obesity and elevated plasma FFA levels through methods that include decreased caloric intake and increased caloric expenditure, the development of methods to measure FFAs in small blood samples, and the development of efficient pharmacologic approaches to normalize increased plasma FFA levels.

Figure 1. Relationship between obesity, insulin resistance, inflammation and atherosclerotic vascular disease

Obesity causes insulin resistance and a state of low grade inflammation. Both contribute 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 atherosclerotic vascular disease. T2DM: Type 2 diabetes mellitus, ASVD: atherosclerotic vascular disease.

Figure 2. Potential mechanisms of FFA-induced insulin resistance and inflammation

The key event is an increase in plasma FFA concentration. This leads to the accumulation of fatty acid CoA and DAG, and activation of PKC in skeletal muscle, liver and vascular endothelial cells. It is assumed that activation of PKC interrupts insulin signaling by serine phosphorylation of IRS 1/2, resulting in a decrease in tyrosine phosphorylation of IRS 1/2. In endothelial cells, PKC has been shown to activate NAD(P)H oxidase, which produces reactive oxygen species and destroys NO. Elevation of plasma FFA levels also leads to the production of inflammatory and proatherogenic proteins through activation of the IKK/IκB-α/NFκB and JNK pathways. The broken lines indicate that activation of PKC by the IKK/IκB-α/NFκB pathway and by ROS is a possibility that has not yet been demonstrated in human muscle or liver. Increased FFA-induced insulin resistance reduces glucose uptake in muscle and increases glucose production in the liver. Together, this results in hyperglycemia. In endothelial cells, FFA-mediated insulin resistance results in decreased NO and decreased vasodilatation, which may contribute to the development of hypertension. In muscle and liver, FFA activation of the IKK/IκB-α/NFκB and JNK pathways results in low grade inflammation, which may promote ASVD and NAFLD. ASVD: atherosclerotic vascular disease; CoA: Coenzyme A; DAG: diacylglycerol; FFA: free fatty acids; IRS: insulin receptor substrate; NAD(P)H: nicotinamide adenine dinucleotide phosphate, reduced; NAFLD: non-alcoholic fatty liver disease; NFκB: nuclear factor κB; NO: nitric oxide; PI: phosphoinositide; PKC: protein kinase C; ROS: reactive oxygen species.

Figure 3. Summary of relation between obesity, FFA and ASVD

Obesity, fat feeding and lipid heparin infusion all raise plasma FFA levels. Elevated plasma FFA produce insulin resistance via DAG/PKC by decreasing insulin signaling at the IRS 1/2 level. Insulin resistance promotes ASVD via chronic hyperinsulinemia, a state of increased tendency to blood coagulation and decreased fibrinolysis and by mechanisms not shown here including hypertension, and atherogenic dyslipidemia. Elevated plasma FFA also cause inflammation via activation of the NFκB and JNK pathways. Inflammation can promote ASVD by increasing the production of inflammatory cytokines and by activation of MMPs. ASVD: atherosclerotic vascular; DAG: diacylglycerol; JNK: c-jun NH₂ terminal kinase; MMP: matrix metalloproteinases; PKC: protein kinase C; TF: tissue factor