Superoxide dismutase 2 deficiency in mesenchymal stromal cells induces sympathetic denervation and functional impairment of brown adipose tissue

• DOI: 10.1111/pin.13503
• Publication Date: 2025-01-06T13:41:27Z
• Authors: Yuya Urano; Shinji Mii; Shun Asai; Nobutoshi Esaki; Ryota Ando; Yukihiro Shiraki; Tadashi Iida; Katsuhiro Kato; Mika Hori; Yoshitaka Hayashi; Takahiko Shimizu; Atsushi Enomoto

AbstractBrown adipose tissue (BAT) is an energy‐consuming organ, and its functional dysregulation contributes to the development of metabolic diseases and obesity. BAT function is regulated by the sympathetic nervous system but declines with age, which is partly caused by reduced sympathetic nerve fibers innervating BAT. Thus far, the role of mesenchymal stromal/stem cells in age‐related BAT dysfunction remains unknown. Here, we show that BAT dysfunction may be induced by a defect in the antioxidant capacity of stromal cells that localize in and around the nerve fibers (perineurial cells) of BAT. These cells express Meflin, a marker of mesenchymal stromal/stem cells. Specific deletion of the antioxidant enzyme superoxide dismutase 2 in Meflin‐lineage cells caused sympathetic denervation and whitening of BAT and its functional impairment, as exemplified by a decline in the fat oxidation rate during the daytime. This phenotype was accompanied by overexpression of the neurorepulsive factor semaphorin 3A in perineurial cells. Notably, Meflin‐deficient mice exhibited resistance to doxorubicin‐induced BAT dysfunction. These results highlight the role of Meflin+ stromal cells, including perineurial cells, in maintaining BAT function and suggest that targeting BAT stromal cells provides a new avenue for improving BAT function.