Obesity and type 2 diabetes : a systems biology perspective of a molecular mechanism

Abstract

People who have excess body weight have a higher risk of insulin resistance and type 2 diabetes, because fat interferes with the body's ability to make and use insulin. Insulin, a hormone released by pancreatic beta-cells, is needed to move diet-derived glucose from blood into fat and muscle cells where it is used to produce energy. The precise ways of how fat interferes with insulin action are not yet known. Our hypothesis is that accumulation of fatty acids (break down product of fats) in these cells leads to increased levels of activated fatty acids, so called fatty acyl-CoA esters. The latter may impair cellular energy metabolism and stimulate the production of reactive oxygen species (ROS) due to inhibition of mitochondrial adenine nucleotide translocator (ANT) leading to impaired cell function, for example impaired insulin release from pancreatic beta-cells. In agreement with our hypothesis we have shown that addition of fatty acyl-CoA esters to mitochondria isolated from livers of normal rats leads to decreased activity of the ANT, decreased levels of extramitochondrial ATP and increased production of ROS. The effect of saturated fatty acyl-CoA ester (palmitoyl-CoA) was stronger than the effect of unsaturated fatty acyl-CoA ester (oleoyl-CoA). Interestingly, the observed effects depended on the working condition of these mitochondria. Next we showed, that long-term high fat diet feeding leads to higher blood glucose levels, as well as to oxidative stress and accumulation of fatty acyl-CoA esters in rat livers. However, long-term high fat diet feeding does not cause adaptive changes that would improve mitochondrial ability to deal with these challenges. This indicates that fatty acyl-CoA may exert same effects in intact liver as the ones observed in isolated mitochondria. Similarly to rat livers, long-term exposure of human endothelial cells (cells that line interior surface of blood vessels) to high levels of fatty acids leads to accumulation of fatty acyl-CoA ester and lower levels of ATP in these cells. This negatively affects the ability of these cells to survive and grow. Again, the effect of saturated fatty acid palmitate is stronger that the effect of unsaturated fatty acid oleate. In summary, our data indicate that the proposed mechanism linking obesity and type 2 diabetes (i.e. inhibition of the ANT by fatty acy-CoA esters) may indeed occur in cells leading to impaired cell function characteristic to type 2 diabetes.Heine, R.J. [Promotor]Westerhoff, H.V. [Promotor]Bakker, S.J.L. [Copromotor]Krab, K. [Copromotor