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Leptin Restores Endothelial Function via Endothelial PPAR?-Nox1-Mediated Mechanisms in a Mouse Model of Congenital Generalized Lipodystrophy.

ABSTRACT: Leptin is the current treatment for metabolic disorders associated with acquired and congenital generalized lipodystrophy (CGL). Although excess leptin levels have been associated with vascular inflammation and cardiovascular disease in the context of obesity, the effects of chronic leptin treatment on vascular function remain unknown in CGL. Here, we hypothesized that leptin treatment will improve endothelial function via direct vascular mechanisms. We investigated the cardiovascular consequences of leptin deficiency and supplementation in male gBscl2-/- (Berardinelli-Seip 2 gene-deficient) mice-a mouse model of CGL. CGL mice exhibited reduced adipose mass and leptin levels, as well as impaired endothelium-dependent relaxation. Blood vessels from CGL mice had increased NADPH Oxidase 1 (Nox1) expression and reactive oxygen species production, and selective Nox1 inhibition restored endothelial function. Remarkably, chronic and acute leptin supplementation restored endothelial function via a PPAR?-dependent mechanism that decreased Nox1 expression and reactive oxygen species production. Selective ablation of leptin receptors in endothelial cells promoted endothelial dysfunction, which was restored by Nox1 inhibition. Lastly, we confirmed in aortic tissue from older patients undergoing cardiac bypass surgery that acute leptin can promote signaling in human blood vessels. In conclusion, in gBscl2-/- mice, leptin restores endothelial function via peroxisome proliferator activated receptor gamma-dependent decreases in Nox1. Furthermore, we provide the first evidence that vessels from aged patients remain leptin sensitive. These data reveal a new direct role of leptin receptors in the control of vascular homeostasis and present leptin as a potential therapy for the treatment of vascular disease associated with low leptin levels.

SUBMITTER: Bruder-Nascimento T

PROVIDER: S-EPMC6886673 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Leptin Restores Endothelial Function via Endothelial PPARγ-Nox1-Mediated Mechanisms in a Mouse Model of Congenital Generalized Lipodystrophy.

Bruder-Nascimento Thiago T Faulkner Jessica L JL Haigh Stephen S Kennard Simone S Antonova Galina G Patel Vijay S VS Fulton David J R DJR Chen Weiqin W Belin de Chantemèle Eric J EJ

Hypertension (Dallas, Tex. : 1979) 20191028 6

Leptin is the current treatment for metabolic disorders associated with acquired and congenital generalized lipodystrophy (CGL). Although excess leptin levels have been associated with vascular inflammation and cardiovascular disease in the context of obesity, the effects of chronic leptin treatment on vascular function remain unknown in CGL. Here, we hypothesized that leptin treatment will improve endothelial function via direct vascular mechanisms. We investigated the cardiovascular consequenc ...[more]

PMID: 31656096

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Project description:ContextLipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia.ObjectiveDetermine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy.MethodsOpen-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance.ResultsIn GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ± 3.0, 6.5 ± 1.6, 6.5 ± 1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ± 1.7, 9.1 ± 1.3, 8.3 ± 1.7 mm, P < .01), and LV mass (140.7 ± 45.9, 128.7 ± 37.9, 110.9 ± 29.1 g, P < .01), and increased septal e' velocity (8.6 ± 1.7, 10.0 ± 2.1, 10.7 ± 2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD.ConclusionMetreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

Dataset Information

Leptin Restores Endothelial Function via Endothelial PPAR?-Nox1-Mediated Mechanisms in a Mouse Model of Congenital Generalized Lipodystrophy.

Publications

Leptin Restores Endothelial Function via Endothelial PPARγ-Nox1-Mediated Mechanisms in a Mouse Model of Congenital Generalized Lipodystrophy.

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