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.

中文翻译：

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SIRT3 抑制线粒体钙超载可防止肥胖或与年龄相关的棕色脂肪组织变白

肥胖和衰老期间棕色脂肪组织 (BAT) 的变白和丢失会促进代谢紊乱和相关疾病。Ca2+ 稳态失衡是 BAT 美白过程中线粒体功能障碍和清除的原因。辣椒素是一种激活 TRPV1 的饮食因子，可以抑制高脂饮食 (HFD) 引起的肥胖，但辣椒素是否抑制 BAT 损失及其潜在机制尚不清楚。在这项研究中，我们确定辣椒素对 HFD 诱导的肥胖和 BAT 美白的抑制作用取决于 SIRT3（一种关键的线粒体脱乙酰酶）的参与。SIRT3 还介导了辣椒素对减轻活性氧产生、提高线粒体活性和限制由 HFD 诱导的线粒体钙超载的所有有益作用。从机制上讲，SIRT3 通过以 AMPK 依赖性方式降低 MCU 启动子上的 H3K27ac 水平来抑制线粒体钙单向转运蛋白 (MCU) 介导的线粒体钙超载。此外，HFD 还抑制 AMPK 活性以减少 SIRT3 表达，这可以被辣椒素逆转。辣椒素干预也通过这种机制抑制了衰老诱导的 BAT 变白。总之，这项研究强调了 AMPK/SIRT3 通路在维持 BAT 形态和功能中的关键作用，并表明对该通路的干预可能是预防肥胖或年龄相关代谢疾病的有效目标。HFD 还抑制 AMPK 活性以减少 SIRT3 表达，这可以被辣椒素逆转。辣椒素干预也通过这种机制抑制了衰老诱导的 BAT 变白。总之，这项研究强调了 AMPK/SIRT3 通路在维持 BAT 形态和功能中的关键作用，并表明对该通路的干预可能是预防肥胖或年龄相关代谢疾病的有效目标。HFD 还抑制 AMPK 活性以减少 SIRT3 表达，这可以被辣椒素逆转。辣椒素干预也通过这种机制抑制了衰老诱导的 BAT 变白。总之，这项研究强调了 AMPK/SIRT3 通路在维持 BAT 形态和功能中的关键作用，并表明对该通路的干预可能是预防肥胖或年龄相关代谢疾病的有效目标。