TY - JOUR
T1 - Enhanced de novo lipogenesis in the leptin-unresponsive pancreatic islets of prediabetic Zucker diabetic fatty rats. Role in the pathogenesis of lipotoxic diabetes
AU - Zhou, Yan Ting
AU - Shimabukuro, Michio
AU - Lee, Young H
AU - Koyama, Kazunori
AU - Higa, Moritake
AU - Ferguson, Tagan
AU - Unger, Roger H
PY - 1998
Y1 - 1998
N2 - Overaccumulation of fat in pancreatic islets of obese ZDF fa/fa rats is believed to cause β-cell failure and diabetes. Previously, we demonstrated that ZDF islets have an increased capacity to esterify fatty acids imported via the circulation. Here we examine the capacity of ZDF islets to synthesize fatty acids de novo. Compared with age-matched wild-type (+/+) control islets, acetyl CoA carboxylase (ACC) mRNA was fivefold and sixfold higher and fatty acid synthetase (FAS) was fourfold and sevenfold higher in prediabetic and diabetic ZDF islets, respectively. Incorporation of label from [14C]glucose into lipids was 84% higher in ZDF islets and was not suppressed normally by fatty acids. Chronic hyperleptinemia, induced by adenoviral transfer of leptin cDNA, reduced ACC and FAS mRNA in +/+ islets by 93 and 80%, respectively, but did not decrease the high ACC and FAS expression in islets of fa/fa rats. Recombinant leptin cultured with islets isolated from +/+ rats lowered ACC and FAS expression by 66 and 47%, respectively, but had no effect in fa/fa islets. We conclude that de novo lipogenesis in islets is controlled by leptin and remains low in leptin-responsive islets. It is increased in leptin-insensitive fa/fa islets, contributing to the fat overload that leads to β-cell dysfunction and diabetes.
AB - Overaccumulation of fat in pancreatic islets of obese ZDF fa/fa rats is believed to cause β-cell failure and diabetes. Previously, we demonstrated that ZDF islets have an increased capacity to esterify fatty acids imported via the circulation. Here we examine the capacity of ZDF islets to synthesize fatty acids de novo. Compared with age-matched wild-type (+/+) control islets, acetyl CoA carboxylase (ACC) mRNA was fivefold and sixfold higher and fatty acid synthetase (FAS) was fourfold and sevenfold higher in prediabetic and diabetic ZDF islets, respectively. Incorporation of label from [14C]glucose into lipids was 84% higher in ZDF islets and was not suppressed normally by fatty acids. Chronic hyperleptinemia, induced by adenoviral transfer of leptin cDNA, reduced ACC and FAS mRNA in +/+ islets by 93 and 80%, respectively, but did not decrease the high ACC and FAS expression in islets of fa/fa rats. Recombinant leptin cultured with islets isolated from +/+ rats lowered ACC and FAS expression by 66 and 47%, respectively, but had no effect in fa/fa islets. We conclude that de novo lipogenesis in islets is controlled by leptin and remains low in leptin-responsive islets. It is increased in leptin-insensitive fa/fa islets, contributing to the fat overload that leads to β-cell dysfunction and diabetes.
UR - http://www.scopus.com/inward/record.url?scp=0031738017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031738017&partnerID=8YFLogxK
U2 - 10.2337/diabetes.47.12.1904
DO - 10.2337/diabetes.47.12.1904
M3 - Article
C2 - 9836522
AN - SCOPUS:0031738017
SN - 0012-1797
VL - 47
SP - 1904
EP - 1908
JO - Diabetes
JF - Diabetes
IS - 12
ER -