Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression.
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.
Gifford Laboratories for Diabetes Research, Center for Diabetes Research, Dallas, TX 75235, USA.
M
M
Shimabukuro
M Y
MY
Wang
Y T
YT
Zhou
C B
CB
Newgard
R H
RH
Unger
D000273:Adipose Tissue / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics; D017931:DNA Primers; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D007515:Islets of Langerhans / Q000473:pathology*; D020738:Leptin; D008297:Male; D011506:Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051381:Rats; D011924:Rats, Zucker; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin
D002352:Carrier Proteins; D017931:DNA Primers; D005227:Fatty Acids; D020738:Leptin; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin