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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肥胖人类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

尽管肥胖症及其相关代谢紊乱的患病率在男女中均在增加，但男女之间的临床表型有所不同，这凸显了对个体治疗选择的需求。包括白色脂肪组织（WAT）在内的各种组织的线粒体功能障碍已被认为是与肥胖相关的合并症（如糖尿病）的关键因素。考虑到女性WAT中线粒体相关基因的更高表达，我们假设肥胖（年龄和BMI匹配）供体的白色（前）脂肪细胞的生物能谱中存在性别差异。

学科/方法

使用Seahorse技术，我们测量了在低，正常，低血压条件下，男性（n = 10）和女性（n = 10）深表型肥胖供体的（前）脂肪细胞的耗氧率（OCR）和细胞外酸化率（ECAR）。和高血糖（0、5和25 mM葡萄糖）和胰岛素刺激的疾病。另外，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后发现，来自女性供体的前脂肪细胞显示出明显更高的线粒体对糖酵解活性（较高的OCR / ECAR比，p = 0.036），这由较高的UQCRC2与PKM2 mRNA水平比来支持（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雌性供体的前脂肪细胞中才显着抑制线粒体活性（即ATP相连的呼吸），反映了它们对胰岛素敏感性更高的趋势。

结论

总的来说，我们显示前脂肪细胞，而不是体外分化的脂肪细胞，代表了一个模型系统，揭示了性别差异对代谢性疾病的临床重要性。尤其是雌性的前脂肪细胞保持增强的线粒体柔韧性，如ATP连接的呼吸作用对葡萄糖的明显反应所证明。