OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype

May Yun Wang; Kazunori Koyama; Michio Shimabukuro; Christopher B. Newgard; Roger H. Uncer

doi:10.1073/pnas.95.2.714

OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype

May Yun Wang, Kazunori Koyama, Michio Shimabukuro, Christopher B. Newgard, Roger H. Uncer

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Abstract

In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an ≃50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wild-type full-length 'b' isoform of the leptin receptor (OB-Rb) in ZDF islets by perfusing ZDF pancreata with recombinant adenovirus containing the cDNA encoding OB-Rb. In cultured islets isolated from these animals, leptin lowered islet TG by 87% and completely blocked TG formation from free fatty acids. Overproduction of NO was reduced, and the preproinsulin mRNA response to free fatty acids was restored. This establishes defective leptin action as the proximate cause of lipotoxic diabetes in ZDF rats.

Original language	English (US)
Pages (from-to)	714-718
Number of pages	5
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	95
Issue number	2
DOIs	https://doi.org/10.1073/pnas.95.2.714
State	Published - Jan 20 1998

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abstract = "In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an ≃50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wild-type full-length 'b' isoform of the leptin receptor (OB-Rb) in ZDF islets by perfusing ZDF pancreata with recombinant adenovirus containing the cDNA encoding OB-Rb. In cultured islets isolated from these animals, leptin lowered islet TG by 87% and completely blocked TG formation from free fatty acids. Overproduction of NO was reduced, and the preproinsulin mRNA response to free fatty acids was restored. This establishes defective leptin action as the proximate cause of lipotoxic diabetes in ZDF rats.",

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T1 - OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype

AU - Wang, May Yun

AU - Koyama, Kazunori

AU - Shimabukuro, Michio

AU - Newgard, Christopher B.

AU - Uncer, Roger H.

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AB - In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an ≃50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wild-type full-length 'b' isoform of the leptin receptor (OB-Rb) in ZDF islets by perfusing ZDF pancreata with recombinant adenovirus containing the cDNA encoding OB-Rb. In cultured islets isolated from these animals, leptin lowered islet TG by 87% and completely blocked TG formation from free fatty acids. Overproduction of NO was reduced, and the preproinsulin mRNA response to free fatty acids was restored. This establishes defective leptin action as the proximate cause of lipotoxic diabetes in ZDF rats.

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OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype

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