Leptin treatment has vasculo-protective effects in lipodystrophic mice

Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2110374119. doi: 10.1073/pnas.2110374119. Epub 2022 Sep 26.


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.

Keywords: EndMT; GDF15; atherosclerosis; leptin; lipodystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Endothelial Cells* / drug effects
  • Epithelial-Mesenchymal Transition* / drug effects
  • Growth Differentiation Factor 15* / metabolism
  • Leptin* / pharmacology
  • Leptin* / therapeutic use
  • Lipodystrophy* / drug therapy
  • Lipodystrophy* / genetics
  • Mice
  • Transforming Growth Factor beta2 / metabolism


  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • Leptin
  • Transforming Growth Factor beta2