147-OR: Glucose Intolerance of Hereditary Progeria Werner Syndrome and Cellular Senescence in Their Adipose Tissue

Abstract

Background: Werner syndrome (WS) is a hereditary premature aging disorder in which various signs of accelerated aging develop after puberty. These signs include gray hair, cataracts, diabetes, myocardial infarction, and malignant tumors. Patients with WS frequently show severe insulin resistance, visceral fat accumulation, and subcutaneous fat atrophy, leading to myocardial infarction due to atherosclerosis. However, the mechanism of accelerated aging and its effect on adipose tissue dysfunction and glucose intolerance remain unclear. Materials and Methods: We evaluated visceral fat area and insulin resistance using the glucose clamp method in four Japanese patients with WS. Stromal vascular fraction (SVF) was obtained from the subcutaneous adipose tissue of WS patients (WSVF) . Healthy individuals and phenotypes were examined. Results: The median glucose infusion rate (GIR) was 3.78 mg/kg/min (interquartile range 3.05, 4.25; insulin infusion rate=1.25 mU/kg/min; normal range >6 mg/kg/min) . All Japanese patients showed severe insulin resistance, sarcopenia, and visceral fat accumulation. The visceral fat area and GIR were inversely correlated (R2=0.72) . In vitro analysis of WSVF revealed early replicative senescence and an increase in SAβgal staining. A significant increase was observed in the expression of senescence-associated secretory phenotypes (SASP) , such as IL1B, IL6, and CXCL8 (p<0.01) , and the senescence marker CDKN2A (p=0.094) . RNA-seq analysis showed that genes related to cell adhesion and cell structure were upregulated in WSVF, whereas genes related to chromosomes, nuclear division, and cell cycle were downregulated. Adipose differentiation was suppressed in WSVF. Conclusions: SVF from the adipose tissue of WS patients exhibited cellular senescence and increased inflammatory cytokine production. Cellular senescence and chronic inflammation of adipose tissue induced by SASP may exacerbate insulin resistance in WS patients. Disclosure D.Sawada: None. T.Takatani: None. H.Hamada: None. K.Yokote: None. H.Kato: n/a. Y.Maezawa: None. D.Kinoshita: None. S.Funayama: None. H.Kaneko: None. T.Minamizuka: None. M.Koshizaka: None. T.Shiohama: None. Funding JSPS (20K17485) , AMED (21bm0804016h0005)