Leptin Restores Endothelial Function, Reduces Vascular Inflammation But Not Vascular Remodeling In Mouse Models Of Congenital And Acquired Lipodystrophy Via Anti‐Oxidant Properties.

Abstract

Lipodystrophy is a metabolic disease characterized by a loss of adipose tissue and a major cause of vascular disease. A key feature of lipodystrophy is a decrease in the levels of the adipokine leptin, which can exerts both deleterious and beneficial cardiovascular actions. We tested the hypothesis that leptin replacement therapy, the treatment currently offered to lipodystrophic patients, restores endothelial function via direct mechanisms in lipodystrophic mice. Constitutive and inducible deletion of Berardinelli‐Seip gene (Bscl2) was employed to generate mouse models of congenital (gBscl2−/−) and acquired (iBscl2) lipodystrophy. Constitutive (gBscl2−/−) and 8 weeks of Bscl2 deletion in iBscl2−/− markedly reduced adipose mass [% of fat: wild‐type (WT): 8.6 ± 0.3 vs gBscl2−/−: 2.4 ± 0.1* vs iBscl2−/−: 4.2 ± 0.2* (*P<0.05 vs WT)] and leptin levels [ng/mL: WT: 4.0 ± 0.3 vs gBscl2−/−: 0.3 ± 0.1* vs iBscl2−/−: 1.4 ± 0.5* (*P<0.05 vs WT)], and impaired aortic endothelium‐dependent but not independent relaxation. Deletion of Bscl2 for a week in iBscl2−/− mice did not reduce adipose mass nor impaired endothelial function indicating that loss of adipose mass is a pre‐requisite to endothelial dysfunction. ROS scavenging via tempol (100 μmol/l) or NOX1/4 inhibition (GKT137831, 10 μmol/l) restored endothelial function in aortic rings from both gBscl2−/− and iBscl2 mice. Contribution of ROS to endothelial function was further supported by increases in vascular −O2, H2O2 and Nox1 expression in aortic rings and in endothelial cells from gBscl2−/− mice. Despite no increase in blood pressure, gBscl2−/− mice exhibit increased aortic media thickness and elevated TGF‐β and collagen 1 and 3α1 expression. In addition, aortas from gBscl2−/− shown increases in TNF‐α, IL‐1β, IL‐18 and Caspase‐1, characteristic of vascular inflammation. A week leptin supplementation lowered blood glucose, fully restored endothelial function, decreased vascular inflammation and reduced ROS and Nox1 expression in aortas and in endothelial cells from gBscl2−/− mice, without increasing blood pressure. However, one week of leptin treatment did not reduce aortic media thickness nor TGF‐β and collagen 1 and 3α1 gene expression. Treatment of gBscl2−/− mice with the sodium/glucose cotransporter 2 inhibitor (dapagliflozin) reduced glucose levels similarly to leptin but did not restore endothelial function in gBscl2−/− mice. Our data demonstrate that leptin replacement therapy restores endothelial function and reduces vascular inflammation in mouse models of congenital lipodystrophy, via reducing expression Nox1‐derived ROS and independent of improvement of metabolic function. Our data also show the physiological role of leptin in the homeostasis of metabolic and vascular function and may present leptin replacement therapy as a therapeutic approach for the treatment of other metabolic disease associated with a reduced fat mass.Support or Funding InformationWork supported by 17POST33410363 to TBN and 16IRG27770047 and 1R01HL13030101 to EJ.BdC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.