By G. Boden, Email: guenther.boden@tuhs.temple.edu and L.H. Carnell, Temple University School of Medicine, Philadelphia, PA, USA. Conference paper presented at the American Oil Chemists’ Society (AOCS) Symposium, May 2009. Theme: Fatty Acids in Health Promotion: Recent Developments.
Obesity is tightly linked with elevated plasma FFA levels, insulin resistance, low grade inflammation, endoplasmic reticulum (ER) stress and a greatly increased risk for ASVD (heart attacks, strokes and peripheral vascular disease). There are many causes for this association some of which have recently been elucidated. Among those, FFA have emerged as a major link between obesity and insulin resistance and type 2 diabetes. Most obese people have elevated plasma FFA levels and FFAs cause insulin resistance in skeletal muscle (by decreasing insulin stimulated glucose uptake) and in the liver (by decreasing insulin inhibition of glycogenolysis). The mechanisms involved include intracellular accumulation of diacylglycerol, activation of several serine/threonine kinases (including PKC, JNK, IKK, p38 MAPK) and decreased tyrosine phosphorylation of IRS 1/2 which causes inhibition of insulin signaling.
FFA also activate the proinflammatory and proatherogenic NFkB pathway resulting in synthesis and release of inflammatory cytokines (including TNF-a, IL-1b, IL-6, MCP-1) and strongly activate the tissue factor pathway of blood coagulation and, via hyperinsulinemia, activate several matrix metalloproteinases (such as MMP2, MMP9, MT1-MMP) known to be involved in development of acute coronary events. In addition, FFA and high fat diets have recently been found to produce ER stress which also (via activation of JNK) can produce insulin resistance and inflammation.
In conclusion, considerable progress has been made during the past ten years in our understanding of the mechanisms responsible for the 2-5 fold increase in ASVD risk in obese people.
