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. 1997 Apr 29;94(9):4637-41.
doi: 10.1073/pnas.94.9.4637.

Direct antidiabetic effect of leptin through triglyceride depletion of tissues

M Shimabukuro  1 , K Koyama, G Chen, M Y Wang, F Trieu, Y Lee, C B Newgard, R H Unger
Affiliations

Direct antidiabetic effect of leptin through triglyceride depletion of tissues

M Shimabukuro et al. Proc Natl Acad Sci U S A. .

Abstract

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 approximately 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.

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Figures

Figure 1
Figure 1
Effect of recombinant leptin on triglyceride content (A), oxidation (B), and esterification (C) of [3H]palmitate in islets from normal Wistar rats cultured for 3 days. Data represent the mean ± SEM for three samples. ∗, P <0.05; and ∗∗, P <0.01 vs. O leptin.
Figure 2
Figure 2
Effect of infusion of AdCMV–leptin on plasma FFA (A) and β-OH (B) and urinary ketones (C) of normal Wistar rats. AdCMV–β-gal-infused rats, open bars; AdCMV–leptin-induced rats, dashed bars; pairfed controls, closed bars. Blood and urine samples were collected before (0) and 3, 7, and 14 days after operations. Data represent the mean ± SEM for four to six samples.
Figure 3
Figure 3
Effect of infusion of AdCMV–leptin on food intake (A) and body weight (B) of normal Wistar and heterozygous (fa/+) and homozygous (fa/fa) ZDF rats. AdCMV–β-gal-infused rats, open circles; AdCMV–leptin-induced rats, closed circles; pairfed controls, open squares. Food intake and body weight changes were measured before (0) and 14 days after operations. Data represent the mean ± SEM for four to six samples.
Figure 4
Figure 4
(A) Genotyping of ZDF animals. Effect of recombinant leptin on triglyceride content (B), oxidation (C), and esterification (D) of [3H]-palmitate in islets from wild-type (+/+), heterozygous (fa/+), and homozygous (fa/fa) ZDF rats cultured for 3 days. Lanes in A: 1, wild-type (+/+); 2, heterozygous lean (fa/+); 3, homozygous obese fa/fa rat. A 130-bp MspI fragment in lanes 2 and 3 is not shown. Data in B–D represent the mean ± SEM for three samples. ∗, P <0.05; and ∗∗, P <0.01 vs. O leptin.
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