DataSheet_1_Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice.pdf

Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.

饮食干预是当前遏制肥胖流行的常用策略。营养状况的改变会调控胰岛素（insulin）、瘦素（leptin）等代谢激素以及胰岛素样生长因子（insulin-like growth factor, IGF）系统的功能，但目前对于肥胖受试者减重后这些指标的恢复情况，以及不同性别间是否存在差异——尤其是在IGF系统层面——仍知之甚少。本实验中，雌雄小鼠分别饲喂高脂饮食（high fat diet, HFD）或普通饲料，干预时长为8周；随后将半数高脂饮食组小鼠转换为普通饲料饲喂，持续4周，该亚组记为HFDCH组。饲喂高脂饮食后，雌雄小鼠均出现体重增长（p < 0.001）、能量摄入增加（p < 0.001）以及基础血糖升高（p < 0.5），上述指标在转换为普通饲料后均可恢复至正常水平，但雌雄小鼠的恢复速率存在差异。高脂饮食均可使雌雄小鼠下丘脑组织中神经肽Y（neuropeptide Y, NPY）与刺鼠相关蛋白（agouti-related peptide, AgRP）的mRNA水平降低（p < 0.001），同时升高阿黑皮素原（pro-opiomelanocortin, POMC）的mRNA水平（p < 0.001）；上述指标在HFDCH组小鼠中均可恢复至正常水平，但高脂饮食诱导的瘦素受体（leptin receptor, ObR）表达下调却未能恢复（p < 0.05）。所有高脂饮食组小鼠均出现糖耐量异常（p < 0.001），且雄性小鼠受影响更为显著；转换为普通饲料后，该异常可得到纠正。高脂饮食使雌雄小鼠的胰岛素水平与稳态模型评估指数（HOMA index）均升高（p < 0.01），但仅HFDCH组雄性小鼠的该指标可恢复至正常水平。转换为普通饲料后，高脂饮食诱导的循环瘦素、总胰岛素样生长因子1（total IGF1）、胰岛素样生长因子2（IGF2，仅雌性小鼠出现该变化）以及胰岛素样生长因子结合蛋白3（IGF binding protein 3, IGFBP3）的水平升高均可恢复至正常（p < 0.001），但游离胰岛素样生长因子1（free IGF1）的水平仍维持升高状态（p < 0.01）。雄性小鼠的胰岛素样生长因子结合蛋白2（IGF binding protein 2, IGFBP2）水平在高脂饮食后下调，转换为普通饲料后可恢复至正常（p < 0.001），而雌性小鼠的该指标无明显变化。尽管恢复健康饮食可改善本次实验检测的绝大多数代谢指标，但雌雄小鼠的游离IGF1（fIGF1）水平仍维持升高，且下丘脑ObR表达仍呈下调状态。此外，雌雄小鼠在高脂饮食干预以及转换为普通饲料后的响应模式上均存在性别差异，包括循环IGF2与IGFBP2水平——这两类因子此前已有报道参与糖代谢调控。不仅如此，雌雄小鼠的糖代谢模式也存在差异改变，这提示上述观测结果之间可能存在关联。