415-P: Leptin Treatment Has Vasculoprotective Effects in Lipodystrophic Mice

Abstract

Introduction: Adipose tissue (AT) is involved in interorgan crosstalk by releasing adipokines such as leptin. Loss of AT, as seen in the human disease of lipodystrophy syndromes (LD) , results in low leptin levels, severe metabolic pathologies and increased risk for premature atherosclerosis. Therapeutical substitution of leptin improves the metabolic conditions and reduces the risk of death in LD patients. The effect of this treatment on atherosclerotic lesion development and endothelial integrity is unknown. We hypothesize that leptin exerts vasculo-protective effects and limits atherosclerosis. Methods and Results: Endothelial cell (EC) inflammation (ICAM-1, -5.2-fold control, p<0.05) and endothelial to mesenchymal transition (EndMT) (SM22, -2.3-fold control, p<0.05) was reduced by leptin treatment in vitro at mRNA and protein level as determined by qPCR, immunoblot and immunofluorescence. The beneficial effect of leptin on EndMT was further confirmed by single cell sequencing. In a second step, we used a combined lipodystrophic and atherosclerosis-prone mouse model (LDLR-/-;aP2-nSREBP) and analyzed the effect of leptin treatment on the development of atherosclerosis in vivo. Histological sections of the aortic roots showed reduced plaque protrusion into the vessel lumen (-31%, p<0.05, n=4-6) by leptin. Macrophage infiltration into the atherosclerotic lesion was reduced after 16 weeks of leptin substitution, which is in accordance with the reduced permeability of the endothelial layer after leptin treatment seen in vitro (-10.8-fold, p<0.05, n=3) . Conclusion: In vitro, leptin acts anti-inflammatory and reduces EC permeability and EndMT. In a lipodystrophic mouse model, leptin substitution reduced hallmarks of instable plaques like EndMT, plaque protrusion and macrophage invasion. In addition to an improvement of the metabolic complications of LD, leptin may also support endothelial identity and function and therefore be beneficial for the vasculature in LD patients. Disclosure P.E.Stürzebecher: None. A.Tönjes: None. J.Boeckel: None. S.Kralisch: None. M.R.Schubert: None. V.Filipova: None. A.Hoffmann: None. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Miehle: None. T.Ebert: Consultant; Sanofi, Santis, Research Support; AstraZeneca, Novo Nordisk. U.Laufs: None. Funding Collaborative Research Center SFB1052 “Obesity Mechanisms” (SFB-1052/C06)