Enhanced de novo lipogenesis in the leptin-unresponsive pancreatic islets of prediabetic Zucker diabetic fatty rats. Role in the pathogenesis of lipotoxic diabetes

Yan Ting Zhou, Michio Shimabukuro, Young H Lee, Kazunori Koyama, Moritake Higa, Tagan Ferguson, Roger H Unger

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1904-1908
Number of pages5
JournalDiabetes
Volume47
Issue number12
DOIs
StatePublished - Jan 1 1998

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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