Inhibition of Mitochondrial Calcium Overload by SIRT3 Prevents Obesity- or Age-Related Whitening of Brown Adipose Tissue
Inhibition of Mitochondrial Calcium Overload by SIRT3 Prevents Obesity- or Age-Related Whitening of Brown Adipose Tissue
复制标题
SIRT3 抑制线粒体钙超载可防止与肥胖或年龄相关的棕色脂肪组织变白。
DOI：
10.2337/db19-0526
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发表时间：
2020-02-01
期刊：
影响因子：
7.7
通讯作者：
Zhu, Zhiming
中科院分区：
文献类型：
--
作者：
Gao, Peng;Jiang, Yanli;Zhu, Zhiming
在肥胖和衰老过程中，棕色脂肪组织（BAT）的变白和损失会促进代谢紊乱和相关疾病。Ca 2+稳态的失衡解释了BAT美白过程中线粒体的功能障碍和清除。辣椒素是一种激活TRPV 1的膳食因子，可抑制高脂饮食诱导的肥胖，但辣椒素是否能抑制BAT的丢失及其机制尚不清楚。在这项研究中，我们确定辣椒素对HFD诱导的肥胖和BAT美白的抑制作用依赖于SIRT 3的参与，SIRT 3是一种关键的线粒体脱乙酰酶。SIRT 3还介导辣椒素对减轻活性氧产生、提高线粒体活性和限制HFD诱导的线粒体钙超载的所有有益作用。在机制上，SIRT 3通过以AMPK依赖性方式降低MCU启动子上的H3 K27 ac水平来抑制线粒体钙单向转运体（MCU）介导的线粒体钙超载。此外，HFD还抑制AMPK活性以减少SIRT 3表达，这可以被辣椒素逆转。辣椒素干预也通过这一机制抑制衰老诱导的BAT美白。总之，这项研究强调了AMPK/SIRT 3通路在维持BAT形态和功能方面的关键作用，并表明干预该通路可能是预防肥胖或年龄相关代谢疾病的有效靶点。
The whitening and loss of brown adipose tissue (BAT) during obesity and aging promote metabolic disorders and related diseases. The imbalance of Ca2+ homeostasis accounts for the dysfunction and clearance of mitochondria during BAT whitening. Capsaicin, a dietary factor activating TRPV1, can inhibit obesity induced by high-fat diet (HFD), but whether capsaicin inhibits BAT loss and the underlying mechanism remain unclear. In this study, we determined that the inhibitory effects of capsaicin on HFD-induced obesity and BAT whitening were dependent on the participation of SIRT3, a critical mitochondrial deacetylase. SIRT3 also mediated all of the beneficial effects of capsaicin on alleviating reactive oxygen species generation, elevating mitochondrial activity, and restricting mitochondrial calcium overload induced by HFD. Mechanistically, SIRT3 inhibits mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium overload by reducing the H3K27ac level on the MCU promoter in an AMPK-dependent manner. In addition, HFD also inhibits AMPK activity to reduce SIRT3 expression, which could be reversed by capsaicin. Capsaicin intervention also inhibited aging-induced BAT whitening through this mechanism. In conclusion, this study emphasizes a critical role of the AMPK/SIRT3 pathway in the maintenance of BAT morphology and function and suggests that intervention in this pathway may be an effective target for preventing obesity- or age-related metabolic diseases.