Leptin replacement therapy restores endothelial function in mouse models of congenital and acquired lipodystrophy by reducing NOX‐1 and NOX‐4‐derived reactive oxygen species

Abstract

Lipodystrophy is a congenital disorder or a condition acquired later in life characterized by a total or partial absence of adipose tissue resulting in drastic reductions in leptin levels, metabolic disorders and cardiovascular disease (CVD). In 2014 the Food and Drug Administration approved the use of leptin as a therapy to minimize the metabolic dysfunction developed by lipodystrophic patients. However, whether leptin replacement therapy improves lipodystrophy‐associated CVD remains unknown. Here, we tested the hypothesis that exogenous leptin restores vascular function in lipodystrophic mice by regulating redox signaling. Studies were conducted in 10–12 week‐old male Berardinelli‐Seip gene (gBscl2−/−) deficient mice, a well‐characterized model of congenital lipodystrophy, as well as in inducible Bscl2 deficient mice (iBscl2−/−), a model of acquired lipodystrophy. Reduction of adipose tissue in gBscl2−/− and iBscl2−/− mice was confirmed by nuclear magnetic resonance spectroscopy: [wild‐type (WT): 8.1 ± 0.3 vs gBlsc2−/− 1.9 ± 0.5* and iBscl2−/−: 4.2 ± 0.7* (%)*P<0.05 vs WT]. Both gBscl2−/− and iBscl2−/− exhibit reduced plasma leptin levels, hyperglycemia, hyperinsulinemia and hyperlipidemia, indicative of metabolic dysfunction. Radio‐telemetry measurements did not report increases in blood pressure in lipodystrophic mice. Analysis of the aortic vascular reactivity via wire‐myography revealed a severe endothelial dysfunction in both gBscl2−/− and iBscl2−/−, characterized by an impaired relaxation to acetylcholine but no alteration of the endothelium‐independent relaxation (relaxation to sodium nitroprusside). Acute reactive oxygen species scavenging with the superoxide dismutase mimetic tempol (100 μmol/l) or the NOX1‐NOX4 inhibitor GKT137831 (10 μmol/l) restored endothelial function in aortic rings from both gBscl2−/− and iBscl2−/− mice. In parallel, quantitative real‐time RT‐PCR, revealed increases in Nox1 and Nox4 gene expression, as well as in the expression of the NADPH oxidase regulatory subunit NOXA1, in aortic rings from both gBscl2−/− and iBscl2−/− mice. To determine the role of leptin in the vascular dysfunction, gBscl2−/− and iBscl2−/− mice were submitted to a chronic leptin treatment (osmotic mini‐pump 10ug/mouse per day for 7 days). Restoration of leptin levels normalized glucose levels and did not affect the BP. Leptin replacement restored endothelial function and reduced Nox1 and Nox4 ‐ enzymes expression in the vasculature of gBscl2−/− mice. Similarly leptin reduced plasma glucose levels and improved endothelial function in iBscl2−/− mice as it reduced Nox‐enzyme expression. Taken together, these data demonstrate that leptin replacement therapy restored endothelial function in mouse models of congenital and acquired lipodystrophy, via reducing the expression of the ROS‐generating enzymes. These data also emphasize the physiological role of leptin in the control of metabolic and vascular function and may present leptin replacement therapy as a potential therapeutic avenue for the treatment of other metabolic disease such as type 1 diabetes.Support or Funding InformationThis work was supported by Innovative Research Grant from the American Heart Association (16IRG27770047 to EJ.BdC) and a R01 from the NHLBI (1R01HL130301‐01 to EJ.BdC).