Adipose tissue as an endocrine organ: implications of its distribution on free fatty acid metabolism

Free fatty acids (FFAs) are the main circulating lipid fuel in the post-absorptive state. Elevated plasma FFA concentrations are associated with increased endogenous glucose production rates and insulin resistance in skeletal muscle, whereas long-term exposure of pancreatic beta-cells to elevated FFA impairs insulin secretion, with a consequently increased risk of developing type 2 diabetes. A range of adverse changes occur in the vascular endothelium in response to elevation of plasma FFA concentrations that are similar to key early steps in atherogenesis. These include reduced endothelium-dependent vasodilatation and increased expression of adhesion molecules. We have found that the majority of systemic plasma FFAs originate from upper-body subcutaneous fat, with lesser contributions from leg fat and intra-abdominal adipocytes, even in persons with abdominal obesity. However, systemic FFA concentrations correlate positively with visceral fat, so that FFA release from visceral depots appears to serve as a marker of systemic insulin resistance. In addition, the secretion of a range of bioactive substances from intra-abdominal adipocytes (adipokines) is disturbed, with potentially deleterious consequences for metabolism and overall cardiometabolic risk. Interventions that reduce circulating FFA, either due to or independently of weight loss, are likely to improve insulin sensitivity, beta-cell function, and cardiovascular risk. Weight loss in overweight or obese patients would have the additional benefit of reducing intra-abdominal adiposity and tending to correct the pathologically altered adipokine secretion associated with abdominal obesity.