Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure?

Central obesity is increasingly recognized as a risk factor for atheroscler osis and type 2 diabetes mellitus. Here we present a hypothesis that may ex plain the excess atherosclerosis, endothelial dysfunction and progressive b eta-cell failure. Central obesity is associated with increased cytosolic tr iglyceride stores in non-adipose tissues such as muscles, liver and pancrea tic beta-cells. A high cytosolic triglyceride content is accompanied by ele vated concentrations of cytosolic long-chain acyl-CoA esters, the metabolic ally active form of fatty acids. These esters inhibit mitochondrial adenine nucleotide translocators, resulting in an intramitochondrial ADP deficienc y. In vitro, such ADP deficiency is a potent stimulator of mitochondrial ox ygen free radical production, and we assume that this mechanism is also act ive in vivo. The decline of organ function with normal ageing is thought to be due, at least partly, to a continuous low-grade mitochondrial oxygen fr ee radical production. In tissues containing increased cytosolic triglyceri de stores this process will be accelerated. Tissues with a high-energy dema nd or poor free radical scavenging capacity, such as pancreatic beta-cells, are likely to be more susceptible to this process. This is how we explain their gradual dysfunctioning in central obesity. Likewise we propose that t he enhanced production of oxygen free radicals in endothelial cells, or Vas cular smooth muscle cells, leads to the increased subendothelial oxidation of LDL and atherosclerosis, as well as to the endothelial dysfunction and m icroalbuminuria. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved .