Background/Objectives

Although the prevalence of obesity and its associated metabolic disorders is increasing in both sexes, the clinical phenotype differs between men and women, highlighting the need for individual treatment options. Mitochondrial dysfunction in various tissues, including white adipose tissue (WAT), has been accepted as a key factor for obesity-associated comorbidities such as diabetes. Given higher expression of mitochondria-related genes in the WAT of women, we hypothesized that gender differences in the bioenergetic profile of white (pre-) adipocytes from obese (age- and BMI-matched) donors must exist.

Subjects/Methods

Using Seahorse technology, we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) of (pre-)adipocytes from male (n = 10) and female (n = 10) deeply-phenotyped obese donors under hypo-, normo- and hyperglycemic (0, 5 and 25 mM glucose) and insulin-stimulated conditions. Additionally, expression levels (mRNA/protein) of mitochondria-related genes (e.g. UQCRC2) and glycolytic enzymes (e.g. PKM2) were determined.

Results

Dissecting cellular OCR and ECAR into different functional modules revealed that preadipocytes from female donors show significantly higher mitochondrial to glycolytic activity (higher OCR/ECAR ratio, p = 0.036), which is supported by a higher ratio of UQCRC2 to PKM2 mRNA levels (p = 0.021). However, no major gender differences are detectable in in vitro differentiated adipocytes (e.g. OCR/ECAR, p = 0.248). Importantly, glucose and insulin suppress mitochondrial activity (i.e. ATP-linked respiration) significantly only in preadipocytes of female donors, reflecting their trends towards higher insulin sensitivity.

Conclusions

Collectively, we show that preadipocytes, but not in vitro differentiated adipocytes, represent a model system to reveal gender differences with clinical importance for metabolic disease status. In particular preadipocytes of females maintain enhanced mitochondrial flexibility, as demonstrated by pronounced responses of ATP-linked respiration to glucose.

中文翻译：

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肥胖人群的前脂肪细胞对葡萄糖和胰岛素表现出性别特异性的生物能反应。

 背景/目标

尽管肥胖及其相关代谢紊乱的患病率在男女中都在增加，但男性和女性之间的临床表型有所不同，这凸显了个体化治疗选择的必要性。包括白色脂肪组织（WAT）在内的各种组织中的线粒体功能障碍已被认为是糖尿病等肥胖相关合并症的关键因素。鉴于女性 WAT 中线粒体相关基因的表达较高，我们假设来自肥胖（年龄和 BMI 匹配）供体的白色（前）脂肪细胞的生物能特征一定存在性别差异。

 主题/方法

使用 Seahorse 技术，我们测量了男性 (n = 10) 和女性 (n = 10) 深度表型肥胖供体在低、正常状态下的（前）脂肪细胞的耗氧率 (OCR) 和细胞外酸化率 (ECAR)。以及高血糖（0、5 和 25 mM 葡萄糖）和胰岛素刺激条件。此外，还测定了线粒体相关基因（例如UQCRC2）和糖酵解酶（例如PKM2）的表达水平（mRNA/蛋白质）。

 结果

将细胞 OCR 和 ECAR 分解为不同的功能模块表明，来自女性供体的前脂肪细胞显示出显着更高的线粒体到糖酵解活性（更高的 OCR/ECAR 比率，p = 0.036），这得到了较高的 UQCRC2 与 PKM2 mRNA 水平比率的支持（p = 0.021）。然而，在体外分化的脂肪细胞中没有检测到主要的性别差异（例如OCR/ECAR，p = 0.248）。重要的是，葡萄糖和胰岛素仅在女性供体的前脂肪细胞中显着抑制线粒体活性（即ATP相关呼吸），反映了她们对胰岛素敏感性更高的趋势。

 结论

总的来说，我们发现前脂肪细胞（而不是体外分化的脂肪细胞）代表了一个模型系统，可以揭示性别差异对代谢疾病状态的临床重要性。特别是女性的前脂肪细胞保持增强的线粒体灵活性，ATP 相关呼吸对葡萄糖的显着反应证明了这一点。