During inguinal adipose tissue (iWAT) ontogenesis, beige adipocytes spontaneously appear between postnatal 10 (P10) and P20 and their ablation impairs iWAT browning capacity in adulthood. Since maternal obesity has deleterious effects on offspring iWAT function, we aimed to investigate its effect in spontaneous iWAT browning in offspring. Female C57BL/6 J mice were fed a control or obesogenic diet six weeks before mating. Male and female offspring were euthanized at P10 and P20 or weaned at P21 and fed chow diet until P60. At P50, mice were treated with saline or CL316,243, a β3-adrenoceptor agonist, for ten days. Maternal obesity induced insulin resistance at P60, and CL316,243 treatment effectively restored insulin sensitivity in male but not female offspring. This discrepancy occurred due to female offspring severe browning impairment. During development, the spontaneous iWAT browning and sympathetic nerve branching at P20 were severely impaired in female obese dam's offspring but occurred normally in males. Additionally, maternal obesity increased miR-22 expression in the iWAT of male and female offspring during development. ERα, a target and regulator of miR-22, was concomitantly upregulated in the male's iWAT. Next, we evaluated miR-22 knockout (KO) offspring at P10 and P20. The miR-22 deficiency does not affect spontaneous iWAT browning in females and, surprisingly, anticipates iWAT browning in males. In conclusion, maternal obesity impairs functional iWAT development in the offspring in a sex-specific way that seems to be driven by miR-22 levels and ERα signaling. This impacts adult browning capacity and glucose homeostasis, especially in female offspring.

中文翻译：

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肥胖母鼠雌性后代白色脂肪组织中 miR-22 和 ERα 的性别特异性调节损害小鼠功能性米色脂肪细胞的产后早期发育

在腹股沟脂肪组织 (iWAT) 个体发生过程中，米色脂肪细胞在出生后 10 (P10) 和 P20 之间自发出现，其消融会损害成年期 iWAT 褐变能力。由于母亲肥胖会对后代 iWAT 功能产生有害影响，因此我们旨在研究其对后代自发 iWAT 褐变的影响。雌性 C57BL/6 J 小鼠在交配前六周喂食对照或致肥胖饮食。雄性和雌性后代在 P10 和 P20 时被安乐死，或在 P21 时断奶并喂食饲料直至 P60。在 P50 时，用盐水或 CL316,243（一种 β3-肾上腺素受体激动剂）治疗小鼠十天。母亲肥胖在 P60 时诱导胰岛素抵抗，CL316,243 治疗有效恢复了雄性后代的胰岛素敏感性，但不能恢复雌性后代的胰岛素敏感性。这种差异的发生是由于雌性后代严重褐变损伤。在发育过程中，雌性肥胖母猪的后代中 P20 时的自发 iWAT 褐变和交感神经分支严重受损，但在雄性中正常发生。此外，母亲肥胖会增加发育过程中雄性和雌性后代 iWAT 中 miR-22 的表达。ERα 是 miR-22 的靶标和调节因子，在雄性 iWAT 中同时上调。接下来，我们评估了 P10 和 P20 的 miR-22 敲除 (KO) 后代。miR-22 缺陷不会影响雌性 iWAT 自发褐变，并且令人惊讶的是，它可以预测雄性 iWAT 褐变。总之，母亲肥胖会以性别特异性的方式损害后代的功能性 iWAT 发育，这似乎是由 miR-22 水平和 ERα 信号传导驱动的。这会影响成年褐变能力和葡萄糖稳态，尤其是雌性后代。