Resistance to adenovirally induced hyperleptinemia in rats: Comparison of ventromedial hypothalamic lesions and mutated leptin receptors

Kazunori Koyama, Michio Shimabukuro, Guoxun Chen, May-Yun Wang, Young H Lee, Pushpa S. Kalra, Michael G. Dube, Satya P. Kalra, Christopher B. Newgard, Roger H Unger

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Leptin regulates appetite and body weight via hypothalamic targets, but it can act directly on cultured pancreatic islets to regulate their fat metabolism. To obtain in vivo evidence that leptin may act peripherally as well as centrally, we compared the effect of adenovirally induced hyperleptinemia on food intake, body weight, and islet fat content in ventromedial hypothalamic-lesioned (VMHL) rats, sham-lesioned (SL) controls, and Zucker Diabetic Fatty (ZDF) rats in which the leptin receptor is mutated. Infusion with recombinant adenovirus containing the rat leptin cDNA increased plasma leptin by ~ 20 ng/ml in VMHL and ZDF rats but had no effect on their food intake, body weight, or fat tissue weight. Caloric matching of hyperphagic VMHL rats to SL controls did not reduce their resistance to hyperleptinemia. Whereas prediabetic ZDF rats had a fourfold elevation in islet fat, in VMHL rats islet fat was normal and none of them became diabetic. Isolated islets from ZDF rats were completely resistant to the lipopenic action of leptin, while VMHL islets exhibited 50% of the normal response; caloric matching of VMHL rats to SL controls increased leptin responsiveness of their islets to 92% of controls. We conclude that leptin regulation of adipocyte fat requires an intact VMH but that islet fat content is regulated independently of the VMH.

Original languageEnglish (US)
Pages (from-to)728-733
Number of pages6
JournalJournal of Clinical Investigation
Volume102
Issue number4
DOIs
StatePublished - Aug 15 1998

Keywords

  • Adenoviral gene transfer
  • Islets
  • Leptin resistance
  • Triglycerides
  • Zucker Diabetic Fatty (ZDF) rats (falfa)

ASJC Scopus subject areas

  • Medicine(all)

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