PROTECTION AGAINST LIPOAPOPTOSIS OF BETA-CELLS THROUGH LEPTIN-DEPENDENT MAINTENANCE OF BCL-2 EXPRESSION

Obesity causes its complications through functional and morphologic da mage to remotely situated tissues via undetermined mechanisms, In one rodent model of obesity, the Zucker diabetic fatty fa/fa sat, overaccu mulation of triglycerides in the pancreatic islets may be responsible for a gradual depletion of beta cells, leading to the most common comp lication of obesity, non-insulin-dependent diabetes mellitus. At the o nset of non-insulin-dependent diabetes mellitus, the islets from fa/fa rats contain up to 100 times the fat content of islets from normal le an rats, Ultimately, about 75% of the beta cells disappear from these fat-laden islets as a consequence of apoptosis induced by long-chain f atty acids (FA). Here we quantify Bcl-2, the anti-apoptosis factor in these islets, and find that Bcl-2 mRNA and protein are, respectively, 85% and 70% below controls. In normal islets cultured in 1 mM FA, Bcl- 2 mRNA declined by 68% and completely disappeared in fa/fa islets cult ured In FA, Ire both groups, suppression was completely blocked by the fatty acyl-CoA synthetase inhibitor, triacsin C, evidence of its medi ation by fatty acyl-CoA. To determine whether leptin action blocked FA -induced apoptosis, we cultured normal and fa/fa islets in 1 mM FA wit h off without leptin. Leptin completely blocked FA-induced Bcl-2 suppr ession in normal islets but had no effect on islets from fa/fa rats, w hich are unresponsive to leptin because of a mutation in their leptin receptors (OB-R). However, when wild-type OB-R is overexpressed in fa/ fa islets, leptin completely prevented FA-induced Bcl-2 suppression an d DNA fragmentation.