Table2_The interplay of maternal and offspring obesogenic diets: the impact on offspring metabolism and muscle mitochondria in an outbred mouse model.docx

Consumption of obesogenic (OB) diets increases the prevalence of maternal obesity worldwide, causing major psychological and social burdens in women. Obesity not only impacts the mother’s health and fertility but also elevates the risk of obesity and metabolic disorders in the offspring. Family lifestyle is mostly persistent through generations, possibly contributing to the growing prevalence of obesity. We hypothesized that offspring metabolic health is dependent on both maternal and offspring diet and their interaction. We also hypothesized that the sensitivity of the offspring to the diet may be influenced by the match or mismatch between offspring and maternal diets. To test these hypotheses, outbred Swiss mice were fed a control (C, 10% fat, 7% sugar, and n = 14) or OB diet (60% fat, 20% sugar, and n = 15) for 7 weeks and then mated with the same control males. Mice were maintained on the same corresponding diet during pregnancy and lactation, and the offspring were kept with their mothers until weaning. The study focused only on female offspring, which were equally distributed at weaning and fed C or OB diets for 7 weeks, resulting in four treatment groups: C-born offspring fed C or OB diets (C » C and C » OB) and OB-born offspring fed C or OB diets (OB » C and OB » OB). Adult offspring’s systemic blood profile (lipid and glucose metabolism) and muscle mitochondrial features were assessed. We confirmed that the offspring’s OB diet majorly impacted the offspring’s health by impairing the offspring’s serum glucose and lipid profiles, which are associated with abnormal muscle mitochondrial ultrastructure. Contrarily, maternal OB diet was associated with increased expression of mitochondrial complex markers and mitochondrial morphology in offspring muscle, but no additive effects of (increased sensitivity to) an offspring OB diet were observed in pups born to obese mothers. In contrast, their metabolic profile appeared to be healthier compared to those born to lean mothers and fed an OB diet. These results are in line with the thrifty phenotype hypothesis, suggesting that OB-born offspring are better adapted to an environment with high energy availability later in life. Thus, using a murine outbred model, we could not confirm that maternal obesogenic diets contribute to female familial obesity in the following generations.

致肥胖饮食（obesogenic diet，OB）的摄入在全球范围内升高了母体肥胖的患病率，给女性带来了沉重的心理与社会负担。肥胖不仅会损害母体健康与生育能力，还会增加子代发生肥胖及代谢紊乱的风险。家族生活方式多可跨代延续，可能进一步推高肥胖的全球患病率。本研究提出两项核心假说：其一，子代的代谢健康状况同时受母体饮食、子代饮食及其交互作用的影响；其二，子代对饮食的敏感性可能取决于子代与母体饮食的匹配或错配状态。为验证上述假说，本研究选用远交系瑞士小鼠（outbred Swiss mice），分别饲喂对照组饲料（C组：脂肪占比10%、糖占比7%，样本量n=14）或OB致肥胖饲料（脂肪占比60%、糖占比20%，样本量n=15），饲喂周期为7周，随后与同品系对照雄鼠交配。雌鼠在妊娠及哺乳期持续饲喂对应饲料，子代与母鼠共同饲养至断乳阶段。本研究仅聚焦雌性子代，断乳时将其均等分组，分别饲喂C或OB饲料，最终形成4个处理组：母代饲喂对照饲料、子代饲喂对照饲料组（C→C）、母代饲喂对照饲料、子代饲喂OB饲料组（C→OB）、母代饲喂OB饲料、子代饲喂对照饲料组（OB→C）以及母代饲喂OB饲料、子代饲喂OB饲料组（OB→OB）。本研究对成年子代的全身血液代谢谱（脂质与葡萄糖代谢相关指标）及肌肉线粒体特征开展了检测与评估。结果证实，子代的OB饮食可通过损害血清葡萄糖与脂质代谢谱，显著损害子代健康，该效应与肌肉线粒体超微结构异常密切相关。与之相反，母体OB饮食可提升子代肌肉中线粒体复合物标志物的表达水平与线粒体形态完整性，但未观察到子代OB饮食对肥胖母鼠所产幼崽存在额外的不良影响（即未观测到子代OB饮食敏感性升高的现象）。相较而言，肥胖母鼠所产且饲喂OB饲料的子代，其代谢谱相较于瘦母鼠所产且饲喂OB饲料的子代更为健康。上述结果与节俭表型假说（thrifty phenotype hypothesis）相符，提示肥胖母鼠所产子代在生命后期可更好地适应高能量可及性的环境。综上，本研究通过远交系小鼠模型，未能证实母体致肥胖饮食会在后续世代中加剧雌性子代的家族性肥胖。