Castelli S, Tramutola A, Perluigi M, Bacalini M G, Ciriolo M R, Ciccarone F
Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, 00166, Rome, Italy; IRCCS San Raffaele Roma, 00166, Rome, Italy.
Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, 00185, Rome, Italy.
Free Radic Biol Med. 2025 Sep;237:101-109. doi: 10.1016/j.freeradbiomed.2025.05.432. Epub 2025 May 31.
Down syndrome (DS) is associated with intellectual disability and multiple metabolic abnormalities, including obesity and early-onset type 2 diabetes. Gene dosage effects resulting from trisomy 21 may contribute to metabolic dysregulation in DS by impairing the function of key organs involved in systemic energy homeostasis. Brown and beige adipocytes, which are specialized for thermogenesis, dissipate energy through the oxidation of fatty acids and glucose, and are thus protective against metabolic diseases. In this study, we investigated the thermogenic potential of brown adipose tissue (BAT) in the Ts2Cje mouse model of DS. DS BAT exhibited morphological and functional signs of impairment, including enlarged lipid droplets and reduced expression of thermogenic proteins, consistent with a whitening phenotype. These changes were accompanied by decreased mitochondrial fission, suppressed triglyceride and glucose catabolism, and blunted insulin signaling. Subcutaneous adipose tissue, in which beige adipocytes are distributed, also showed signs of degeneration in DS mice, with a marked increase in senescence and inflammatory markers. In both adipose depots, superoxide dismutase 1 (SOD1), a gene triplicated in DS, was significantly upregulated and positively correlated with markers of lipid peroxidation and adipose tissue dysfunction. Together, these findings suggest that oxidative stress, driven in part by SOD1 overexpression, may compromise the thermogenic function of adipose tissue in DS, thereby contributing to the development of metabolic disorders in this condition.
唐氏综合征（DS）与智力残疾和多种代谢异常有关，包括肥胖和早发性2型糖尿病。21三体导致的基因剂量效应可能通过损害参与全身能量稳态的关键器官的功能，导致DS患者的代谢失调。棕色和米色脂肪细胞专门用于产热，通过脂肪酸和葡萄糖的氧化消耗能量，因此对代谢疾病具有保护作用。在本研究中，我们调查了DS的Ts2Cje小鼠模型中棕色脂肪组织（BAT）的产热潜力。DS的BAT表现出形态和功能受损的迹象，包括脂滴增大和产热蛋白表达降低，这与白化表型一致。这些变化伴随着线粒体裂变减少、甘油三酯和葡萄糖分解代谢受抑制以及胰岛素信号传导减弱。分布有米色脂肪细胞的皮下脂肪组织在DS小鼠中也显示出退化迹象，衰老和炎症标志物显著增加。在两个脂肪库中，DS中三倍体的基因超氧化物歧化酶1（SOD1）显著上调，并且与脂质过氧化和脂肪组织功能障碍的标志物呈正相关。总之，这些发现表明，部分由SOD1过表达驱动的氧化应激可能损害DS患者脂肪组织的产热功能，从而导致这种情况下代谢紊乱的发展。
