Leptin treatment has vasculo-protective effects in lipodystrophic mice

Lipodystrophy syndromes (LD) 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 impairs the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation, 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 pro-atherosclerotic cytokine growth/differentiation factor 15 (GDF15). Inhibition of GDF15 reduced EndMT induction triggered by plasma from LD patients. 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. Human umbilical vein endothelial cells were treated with TGF-β2 or additionally with leptin, and afterwards analyzed using scRNAseq.