Metreleptin restores vascular endothelial function in a mouse model of acquired lipodystrophy likely via PPARγ‐dependent reduction in reactive oxygen species.

Abstract

Lipodystrophy, a disease characterized by a reduction in adipose tissue, leads to reduced production of the adipocyte‐derived hormone leptin, which is a major regulator of both metabolic and cardiovascular function. Metreleptin, the human leptin analogue, has recently been approved by the FDA for the treatment of metabolic disorders associated with lipodystrophy. However, while patients with lipodystrophy present with cardiovascular disease, the effects of chronic metreleptin treatment on cardiovascular function remain poorly understood. Herein, we hypothesized that metreleptin treatment improves endothelial function in a mouse model of acquired lipodystrophy. We used male inducible Berardinelli‐Seip2 gene deficient mice (iBscl2−/−) as a mouse model of lipodystrophy. iBscl2−/−mice exhibited decreased total body weight (iBscl2+/+: 27.85±1.9 vs iBscl2−/−: 25.61±2.05, g body weight P=.0530), reduced body fat percentage (iBscl2+/+: 11.2±2.5 vs iBscl2−/−: 8.7±1.1*, % body weight *P<0.05), low levels of leptin (iBscl2+/+: 4.46±0.5 vs iBscl2−/−: 1.46±1.27**, ng/dL **P<0.01), and unaltered glucose metabolism as measured by a glucose tolerance test. Vascular reactivity was determined ex vivo by mounting aortic rings on a wire‐myograph. The rings were bathed in a physiological solution, to which serotonin was added to preconstrict the vessels and subsequently acetylcholine (ACh) or sodium nitroprusside (SNP) were titrated to relax the vessels and generate a concentration‐response curve (CRC). Quantitative real time polymerase chain reaction was utilized to measure gene expression in both aortic and adipose tissues. Aortic rings from iBscl2−/− mice exhibited impaired relaxation to ACh but a normal response to SNP, characterizing endothelial dysfunction. Addition of the reactive oxygen species (ROS) scavenger Tempol (10−4M), the NADPH oxidase 1 (Nox1) inhibitor GKT771 (10−5M), or the PPARγ ligand Pioglitazone (10−5M) to the solution bathing the vessels ameliorated the endothelial function by improving relaxation to ACh. In addition, aortas from iBscl2−/−mice displayed elevated Nox1 expression. Metreleptin treatment (0.3mg/day/7days, IP) increased aortic tissue PPARγ expression, reversed aortic tissue Nox1 elevation, and restored endothelial function in iBscl2−/− mice. Furthermore, metreleptin treatment increased the sensitivity to SNP in aortic rings for both iBscl2+/+and iBscl2−/−. Interestingly, metreleptin treatment potentiated adipose tissue inflammation by increasing monocyte chemoattractant protein 1 (MCP1) and C‐C chemokine receptor type 5 (CCR5) expression in both iBscl2+/+and iBscl2−/−adipose tissue. In conclusion, metreleptin improves endothelial function in a mouse model of lipodystrophy via boosting PPARγ activity and reducing Nox1‐derived ROS apparently acting directly on the vasculature. These data explore the molecular mechanism by which metreleptin affects endothelial function and could lead to a better understanding of the impact of metreleptin on the cardiovascular system of lipodystrophic patients.Support or Funding InformationMCG Medical Scholars Program 1R01HL130301‐01 to EBC; K99: 1K99HL140139‐01A1 to TBN