Adipocyte-derived PDGF-D counteracts age-associated obesity through ameliorating lymphatic function

Normal lymphatic function protects against obesity by preventing abnormal lymph leakage, which drives excessive adipocyte proliferation in adjacent tissues. Notably, platelet-derived growth factor D (PDGF-D) has been reported to play key roles in lymphangiogenesis. However, whether PDGF-D regulates age-associated obesity through modulation of lymphatic function remains unknown. In the study, we found that middle-aged mice exhibited greater susceptibility to high-fat diet (HFD)-induced obesity than young mice, accompanied by reduced lymphatic vessel density, impaired lymphatic function, and decreased PDGF-D expression in adipose tissue. By generating adipocyte-specific PDGF-D knockout and overexpression mice, we demonstrated that PDGF-D deficiency, despite having no direct effect on adipocytes, was sufficient to induce lymphatic dysfunction, which in turn exacerbated HFD-induced obesity in young mice. While adipocyte-specific PDGF-D overexpression restored lymphatic function and reversed HFD-induced severe obesity in middle-aged mice. Moreover, stimulating lymphangiogenesis via adeno-associated virus (AAV)-mediated delivery of an engineered VEGF-C variant (VEGF-C156S) successfully suppressed HFD-induced obesity in young adipocyte-PDGF-D knockout mice. In vitro , we found that adipocyte-derived PDGF-D promoted tube formation, proliferation, and the integrity of lymphatic endothelial cells (LECs), thereby preventing lipid permeation and subsequently suppressing adipogenesis. In conclusion, these findings demonstrate an uncovered mechanism by which adipocyte-derived PDGF-D protects against age-related obesity through regulation of lymphatic function.