Oxidative stress characterizes the dysfunction of thermogenic adipose tissue in a mouse model of down syndrome.

Abstract

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.