Sexual dimorphism in adipose tissue mitochondrial function and metabolic flexibility in obesity.
Sexual dimorphism in adipose tissue mitochondrial function and metabolic flexibility in obesity.
复制标题
肥胖患者脂肪组织中的性二型性、线粒体功能和代谢灵活性。
DOI：
10.1038/s41366-021-00843-0
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Roberts LD
中科院分区：
文献类型：
--
作者：
MacCannell ADV;Futers TS;Whitehead A;Moran A;Witte KK;Roberts LD
肥胖症的流行在全球范围内呈上升趋势。肥胖会增加患代谢综合征、2型糖尿病和心血管疾病的风险。脂肪组织分布影响全身代谢，影响代谢性疾病风险。肥胖的两性二态性与新陈代谢之间的联系尚不明确。我们假设，储存库特异性脂肪组织线粒体功能有助于肥胖代谢灵活性的性别二态性。8-18周龄饲喂高脂饲料（HFD）或标准饲料（STD）的雄性和雌性小鼠，对脂肪组织库进行全动物热量测定和高分辨率线粒体呼吸测定分析。为了确定可翻译性，我们使用RT-qPCR检测了棕色脂肪细胞相关的关键基因表达：过氧化物酶体增殖体激活受体共激活因子1α、解偶联蛋白1和细胞死亡诱导DFFA样效应因子a在18周大鼠和人类志愿者的棕色脂肪组织（BAT）和皮下脂肪组织（sWAT）中的表达。当受到HFD刺激时，雄性小鼠比雌性小鼠表现出更大的体重增加。相对于体重的增加，饲喂高脂饲料的雄性小鼠的BAT和sWAT仓库的脂肪与体重比高于饲喂高脂饲料的雌性小鼠。雄性和雌性的耗氧量、能量消耗、呼吸交换率和食物消耗无显著差异。与苗条女性相比，肥胖女性的BAT线粒体显示出复合物I和II呼吸和最大呼吸增加，而肥胖男性则没有表现出适应性线粒体BAT呼吸。sWAT中bat相关基因表达的性别二态性也与人类体重指数有关。我们表明体重增加的性别二态性反映在线粒体呼吸分析中。当HFD挑战和sWAT线粒体质子泄漏增加时，雌性小鼠通过增加BAT内复合物II和最大线粒体呼吸来调节能量消耗，从而增加代谢灵活性以适应能量摄入的变化。
The prevalence of obesity is growing globally. Adiposity increases the risk for metabolic syndrome, type 2 diabetes and cardiovascular disease. Adipose tissue distribution influences systemic metabolism and impacts metabolic disease risk. The link between sexual dimorphisms of adiposity and metabolism is poorly defined. We hypothesise that depot-specific adipose tissue mitochondrial function contributes to the sexual dimorphism of metabolic flexibility in obesity. Male and female mice fed high fat diet (HFD) or standard diet (STD) from 8–18 weeks of age underwent whole animal calorimetry and high-resolution mitochondrial respirometry analysis on adipose tissue depots. To determine translatability we used RT-qPCR to examine key brown adipocyte-associated gene expression: peroxisome proliferator-activated receptor co-activator 1α, Uncoupling protein 1 and cell death inducing DFFA like effector a in brown adipose tissue (BAT) and subcutaneous adipose tissue (sWAT) of 18-week-old mice and sWAT from human volunteers. Male mice exhibited greater weight gain compared to female mice when challenged with HFD. Relative to increased body mass, the adipose to body weight ratio for BAT and sWAT depots was increased in HFD-fed males compared to female HFD-fed mice. Oxygen consumption, energy expenditure, respiratory exchange ratio and food consumption did not differ between males and females fed HFD. BAT mitochondria from obese females showed increased Complex I & II respiration and maximal respiration compared to lean females whereas obese males did not exhibit adaptive mitochondrial BAT respiration. Sexual dimorphism in BAT-associated gene expression in sWAT was also associated with Body Mass Index in humans. We show that sexual dimorphism of weight gain is reflected in mitochondrial respiration analysis. Female mice have increased metabolic flexibility to adapt to changes in energy intake by regulating energy expenditure through increased complex II and maximal mitochondrial respiration within BAT when HFD challenged and increased proton leak in sWAT mitochondria.
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