Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression.

Published

Journal Article

Obesity causes its complications through functional and morphologic damage to remotely situated tissues via undetermined mechanisms. In one rodent model of obesity, the Zucker diabetic fatty fa/fa rat, overaccumulation of triglycerides in the pancreatic islets may be responsible for a gradual depletion of beta cells, leading to the most common complication of obesity, non-insulin-dependent diabetes mellitus. At the onset of non-insulin-dependent diabetes mellitus, the islets from fa/fa rats contain up to 100 times the fat content of islets from normal lean rats. Ultimately, about 75% of the beta cells disappear from these fat-laden islets as a consequence of apoptosis induced by long-chain fatty 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 cultured in FA. In both groups, suppression was completely blocked by the fatty acyl-CoA synthetase inhibitor, triacsin C, evidence of its mediation by fatty acyl-CoA. To determine whether leptin action blocked FA-induced apoptosis, we cultured normal and fa/fa islets in 1 mM FA with or without leptin. Leptin completely blocked FA-induced Bcl-2 suppression in normal islets but had no effect on islets from fa/fa rats, which 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 and DNA fragmentation.

Full Text

Duke Authors

Cited Authors

  • Shimabukuro, M; Wang, MY; Zhou, YT; Newgard, CB; Unger, RH

Published Date

  • August 4, 1998

Published In

Volume / Issue

  • 95 / 16

Start / End Page

  • 9558 - 9561

PubMed ID

  • 9689119

Pubmed Central ID

  • 9689119

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.95.16.9558

Language

  • eng

Conference Location

  • United States