ISRIB alleviates aging-associated brown fat UCP1 translational repression and thermogenic deficiency
ISRIB alleviates aging-associated brown fat UCP1 translational repression and thermogenic deficiency
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DOI：
10.1016/j.bbrc.2023.06.073
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发表时间：
2023-06-30
影响因子：
3.1
通讯作者：
Lu，Huanyu
中科院分区：
文献类型：
--
作者：
Li，Muze;Gao，Mengjie;Lu，Huanyu
Upon cold exposure, aged people with lower metabolic rate cannot rapidly increase the higher levels of heat production, and are seriously threatened by the hypothermia, extensive cold stress responses and risk of mortality. Here, we show that brown fat thermogenic activity is obviously deficient in aged mice, associating with reduction of UCP1 expression and inhibition of its mRNA translation. As we considered, aging aggravates brown fat oxidative stress and activates the integrated stress response (ISR), inducing the phosphorylation of eIF2α to block the global mRNA translation. Therefore, small-molecule ISR inhibitor (ISRIB) treatment attenuates the higher level of eIF2α phosphorylation, restores the repression ofUcp1mRNA translation and improves UCP1-mediated thermogenic function to defend cold stress in aged mice. Furthermore, ISRIB treatment increases the relative lower metabolic rates, and alleviates glucose intolerance and insulin resistance in aged mice. Thus, we have uncovered a promising drug that reverses the aged-related the deficiency of UCP1-mediated thermogenesis to combat cold stress and associated metabolic diseases.
