RT Journal Article
SR Electronic
T1 Direct antidiabetic effect of leptin through triglyceride depletion of tissues
JF Proceedings of the National Academy of Sciences
JO Proc Natl Acad Sci USA
FD National Academy of Sciences
SP 4637
OP 4641
DO 10.1073/pnas.94.9.4637
VO 94
IS 9
A1 Shimabukuro, Michio
A1 Koyama, Kazunori
A1 Chen, Guoxun
A1 Wang, May-Yun
A1 Trieu, Falguni
A1 Lee, Young
A1 Newgard, Christopher B.
A1 Unger, Roger H.
YR 1997
UL http://www.pnas.org/content/94/9/4637.abstract
AB Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was ≈20 times normal, and esterification capacity was increased 3- to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an “indirect pathway” of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes. AdCMV,recombinant cytomegalovirus;β-gal,β-galactosidase;TG,triglyceride;FFA,free fatty acids;ZDF,Zucker diabetic fatty;β-OH,β-hydroxybutyrate