Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-β2–induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr −/− ; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 ( GDF15 ). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15 .
Introduction: Patients with lipodystrophy (LD) are characterized by a loss of adipose tissue and are associated with a higher risk for cardiovascular diseases (CVD). As a consequence of adipose tissue reduction in LD patients, the systemic concentration of the adipokine leptin decreases, representing the pathological cause of this disease. Hypothesis: We hypothesized that the reduction of leptin may impair endothelial cells, leading to the development of CVD. Therefore, we analyzed the effects of leptin treatment on vascular inflammation, endothelial-to-mesenchymal transition (EndMT), endothelial permeability and atherosclerotic plaque characteristics. Methods & Results: Treatment of endothelial cells with leptin (200 ng/ml, 6 h) potently reduced IL1β-induced inflammation, as measured by expression of ICAM1 (-25.1%) and E-Selectin (-22.7%), (both p<0.05). Leptin further reduced the induction of EndMT, as determined by expression of calponin (-41.3%) and SM22 (-23.8%), (both p<0.05), as well as the EndMT-induced endothelial permeability (-20.7%, p<0.05). These data were confirmed in a combined lipodystrophic and atherosclerosis prone mouse model (LDLR -/- ;aP2-nSREBP). Treatment with leptin (3.0 mg/kg) for 8 w reduced the number of EndMT-positive endothelial cells (-69%, p<0.05) as well as the total number of mesenchymal cells in the atherosclerotic lesions (-34.8%), (both p<0.05). Further analysis of the atherosclerotic lesions revealed a reduction of atherosclerotic plaque protrusion into the vessel lumen (-31%) and reduced macrophage infiltration (-21.9%) (p<0.05), which is a hallmark of instable atherosclerotic plaques that are prone to rupture, whereas the total plaque area was not affected. The expression of the leptin receptor (LepR) was reduced in endothelial cell inflammation, EndMT (-69%, p<0.05) and in atherosclerotic lesions, suggesting reduced leptin effects under these conditions. Conclusions: Leptin treatment exerts beneficial effects protecting endothelial function and identity in lipodystrophy. Downregulation of the leptin receptor in diseased endothelial cells is likely to reduce the identified positive vascular effects of leptin signaling in lipodystrophy.
Introduction and purpose Lipodystrophy (LD) syndromes are characterized by the loss of adipose tissue resulting in metabolic complications and accelerated atherosclerosis. The systemic concentration of the adipokine leptin is reduced in LD as a result of adipose tissue deficiency. A therapeutical option to treat LD is the substitution of leptin, which improves metabolic complications and reduces mortality. However, the vascular effects of leptin remain largely unknown. Here we analyze the direct effects of leptin on the vascular system and the development of atherosclerosis. Methods and results Treatment of human endothelial cells (ECs) with leptin reduced endothelial inflammation and the process of endothelial-to-mesenchymal transition (EndMT) (CNN1, −41.4%, p<0.05, n=4). In addition, leptin administration prevented the EndMT-induced increase of endothelial permeability. The protective effect of leptin on EndMT was confirmed in vivo in a combined lipodystrophic and atherosclerosis-prone mouse model (LDLR−/−; aP2-nSrebp1c). Treatment of the mice with leptin (3.0 mg/kg body weight daily for 8 weeks) decreased EndMT. Leptin showed no effect on plaques size but reduced the protrusion of plaques in atherosclerotic areas of the aortic roots (−31%, p<0.05, n=4–6). Cytokine screening revealed an increase of the growth differentiation factor 15 (GDF15) in serum of LD patients (+26.2%, p<0.05, n=53–58) and in ECs after EndMT (+138%, p<0.05, n=6743–10920). This increase was reversed using leptin treatment in ECs undergoing EndMT, in the LD mice model, and in LD patients after 4 weeks of leptin administration. Indeed, treatment of endothelial cells with GDF15 induced EndMT (CNN1, +7.7-fold-control, p<0.05, n=3), and impaired EC barrier function. Neutralizing antibodies targeting GDF15 inhibited EndMT-mediated expression of mesenchymal genes (CNN1, −54%, p<0.05, n=4). The treatment of ECs with serum from LD patients induced EndMT and the increase of mesenchymal marker expression was inhibited with additional administration with neutralizing antibodies targeting GDF15 (CNN1, −28%, p<0.05, n=3). Conclusion Our findings indicate that EndMT is part of the cardiovascular disease progression in lipodystrophy syndromes. Leptin treatment has direct protective vascular effects by preventing inflammation, EndMT, and maintaining endothelial integrity. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
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