Direct antidiabetic effect of leptin through triglyceride depletion of tissues

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 Ϸ20 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.

Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1

“…Leptin exerted a prominent inhibitory function against palmitic acid-induced apoptosis both at the caspase 3 and DNA fragmentation level. This is consistent with previous observations of the beta-cell protective function of leptin against lipoapoptosis through triglyceride depletion and increases in fatty acid oxidation [12]. In addition, prevention of fatty acid-induced Bcl-2 suppression was also found to be a critical step of leptin-mediated betacell anti-lipoapoptosis [5].…”

“…This protective action of leptin against beta-cell lipoapoptosis was accompanied by a reduction in ceramide synthesis and iNOS mRNA expression as well as prevention of fatty-acidinduced suppression of Bcl-2 expression thus inhibiting apoptotic death [4,5,6,12]. Further, the effects of leptin on fatty acid metabolism (in muscle) are mediated through activation of 5'-AMP-activated protein kinase (AMPK) and subsequent down-regulation of acetyl coenzyme A carboxylase (ACC) [13,14].…”

Serum leptin level and cognition in the elderly: Findings from the Health ABC Study

“…Transgenic expression of neuron-specific leptin receptor in receptor-deficient mice leads to amelioration of diabetes (de Luca et al, 2005). Additionally, leptin has been shown to have an antidiabetic function through control of intracellular fatty acid metabolism, maintenance of glucose sensitivity, and prevention of islet lipotoxicity (Shimabukuro et al, 1997;Shimokawa and Higami, 2001;Unger, 2005). Peripheral insulin resistance and hyperleptinemia are associated with leptin resistance and reduced expression of leptin receptor mRNA in aging rats (Fernandez-Galaz et al, 2001).…”

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

“…Thus, as adipocytes enlarge, they secrete proportionately more leptin. Leptin prevents overaccumulation of lipids by directly reducing triglyceride synthesis and increasing fatty acid oxidation in its target tissues [27], precisely the effects caused by AMPK activation. A recent study suggests that in skeletal muscle the effect of leptin is the result of AMPK activation and, subsequent to this, ACC inactivation, predominantly mediated by an increase in sympathetic nervous system activity [28].…”