Kaminska Dorota, Pan Calvin, Vergnes Laurent, Ro Ashlyn, Ulaganathan Gurugowtham, Lusis Aldons J
Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Mol Metab. 2025 Aug 5;100:102227. doi: 10.1016/j.molmet.2025.102227.
Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 trans-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether iWAT contributes comparably to sex differences in mitochondrial function and futile cycling.
We analyzed iWAT and gWAT from male and female mice across 58 genetically diverse Hybrid Mouse Diversity Panel (HMDP) strains fed a high-fat, high-sucrose diet. We assessed mitochondrial DNA (mtDNA), oxidative phosphorylation (OXPHOS) and futile cycle gene expression, performed genetic mapping, and measured respiration.
In gWAT, females showed higher mtDNA, OXPHOS expression, and a female-specific chr17 trans-eQTL, correlating with metabolic traits. In contrast, iWAT lacked this hotspot and showed higher mtDNA, OXPHOS expression, and respiration in males. Lipid cycling genes (Lipe, Mgll, Pnpla2) were elevated in male iWAT, while Mpc1, Mpc2, and Pck1 were enriched in female gWAT. Ucp1 was higher in female gWAT but not sex-biased in iWAT. Alpl (TNAP), key creatine cycling gene, was upregulated in females in both depots, particularly in iWAT.
Female gWAT shows genetically driven mitochondrial regulation linked to metabolic protection, whereas male iWAT has higher mitochondrial content, OXPHOS expression, and respiration. Elevated lipolytic enzymes in male iWAT suggest greater FFA release, while higher pyruvate import and glyceroneogenesis genes in female gWAT favor FFA recycling. Alpl upregulation in females indicates sex-biased UCP1-independent thermogenesis. These depot- and sex-specific signatures reflect distinct metabolic strategies and highlight the need to consider both in adipose research.
脂肪组织中的性别差异会影响代谢健康，但其潜在的分子机制仍不清楚。我们之前在性腺白色脂肪组织（gWAT）中鉴定出一个女性特异性的17号染色体反式表达数量性状基因座（trans-eQTL）热点，该热点调控线粒体基因表达。在此，我们测试了腹股沟白色脂肪组织（iWAT）对线粒体功能和无效循环中的性别差异是否有类似作用。
我们分析了来自58个遗传背景各异的杂交小鼠多样性面板（HMDP）品系的雄性和雌性小鼠的iWAT和gWAT，这些小鼠均喂食高脂高糖饮食。我们评估了线粒体DNA（mtDNA）、氧化磷酸化（OXPHOS）和无效循环基因表达，进行了基因定位，并测量了呼吸作用。
在gWAT中，雌性小鼠表现出更高的mtDNA、OXPHOS表达以及一个女性特异性的17号染色体反式表达数量性状基因座，这与代谢特征相关。相比之下，iWAT缺乏这个热点，并且雄性小鼠的mtDNA、OXPHOS表达和呼吸作用更高。脂质循环基因（Lipe、Mgll、Pnpla2）在雄性iWAT中升高，而Mpc1、Mpc2和Pck1在雌性gWAT中富集。Ucp1在雌性gWAT中更高，但在iWAT中无性别偏向。关键的肌酸循环基因碱性磷酸酶（Alpl，TNAP）在两个脂肪库的雌性小鼠中均上调，尤其是在iWAT中。
雌性gWAT显示出由基因驱动的与代谢保护相关的线粒体调控，而雄性iWAT具有更高的线粒体含量、OXPHOS表达和呼吸作用。雄性iWAT中脂解酶升高表明脂肪酸释放增加，而雌性gWAT中更高的丙酮酸转运和甘油生成基因有利于脂肪酸循环利用。雌性中Alpl上调表明存在不依赖于UCP1的性别偏向性产热。这些脂肪库和性别特异性特征反映了不同的代谢策略，并强调在脂肪研究中需要同时考虑这两个因素。
