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Leptin treatment has vasculo-protective effects in lipodystrophic mice
Paulina Elena Stürzebecher1, Susan Kralisch2, Marie Ruth Schubert1
1Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, 04103, Germany.
Abstract:
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.
Insights
Leptin treatment benefits patients with lipodystrophy (LD) by improving endothelial function and reducing atherosclerosis. It protects against endothelial to mesenchymal transition (EndMT) and lowers the proatherosclerotic factor GDF15.
Area of Science:
- Cardiovascular Biology
- Metabolic Disorders
- Endocrinology
Background:
- Lipodystrophy syndromes (LDs) involve adipose tissue loss, leading to metabolic complications and accelerated atherosclerosis.
- Reduced leptin levels in LD contribute to disease progression.
- Endothelial to mesenchymal transition (EndMT) is implicated in atherogenesis within LD.
Purpose of the Study:
- To investigate the protective effects of leptin on endothelial cells in the context of lipodystrophy.
- To determine leptin's impact on endothelial to mesenchymal transition (EndMT) and its role in LD-associated atherosclerosis.
- To elucidate the mechanism by which leptin mitigates EndMT and atherogenesis in LD.
Main Methods:
- Treatment of lipodystrophic and atherosclerosis-prone animal models with leptin.
- Assessment of endothelial barrier function and inflammatory markers.
- Analysis of mesenchymal gene expression in endothelial cells.
- Evaluation of macrophage accumulation and plaque characteristics in atherosclerotic lesions.
- Investigating the role of growth/differentiation factor 15 (GDF15) in leptin's effects.
Main Results:
- Leptin treatment reduced inflammation and suppressed TGF-β2-induced mesenchymal gene expression.
- Leptin prevented endothelial barrier function impairment.
- In animal models, leptin decreased macrophage infiltration, plaque protrusion, and EndMT.
- Leptin inhibited the induction of the proatherosclerotic cytokine GDF15 in LD.
- Inhibition of GDF15 reduced EndMT induced by plasma from LD patients.
Conclusions:
- Leptin treatment offers significant benefits for lipodystrophy patients beyond adipose tissue restoration.
- Leptin protects endothelial cell function and identity by reducing EndMT in LD.
- Leptin's beneficial effects are partly mediated by the inhibition of GDF15, a key factor in LD-associated atherogenesis.
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