Does prenatal alcohol exposure cause a metabolic syndrome? (Non-)evidence from a mouse model of fetal alcohol spectrum disorder

Although prenatal alcohol exposure (PAE) reduces offspring growth, it may increase obesity risk at adolescence. Animal models of PAE display glucose intolerance and increased adiposity, suggesting that PAE causes metabolic reprogramming. We tested this hypothesis in a mouse model of binge PAE, wherein pregnant C57Bl/6J females received 3 g/kg alcohol (ETOH) daily from gestational day 12.5 to 17.5; maltodextrin (MD) and medium chain triglycerides (MCT) served as isocaloric nutritional controls, and sham (H2O) treatment controlled for gavage stress. Our comprehensive assessment quantified body composition, energy expenditure, glucose tolerance, and cardiovascular function in offspring at age 17 weeks. Although ETOH pups were initially lighter than all other groups, they did not have a unique obesogenic phenotype. Instead, a similar obesogenic phenotype emerged in all three caloric groups (MCT, MD, ETOH), such that caloric groups had greater post-weaning weight gain (both sexes), reduced gonadal fat weight (males), and reduced glucose clearance (males) compared against H2O offspring. PAE did not affect body composition, respiratory exchange ratio, metabolic adaption to high-fat or low-fat diet, eating behavior, and blood pressure, and ETOH values did not differ from those obtained from isocaloric controls. Exposure to a higher alcohol dose (4.5 g/kg) or a high-fat (60%) diet did not exacerbate differences in body composition or glucose tolerance. “PAE-specific” effects on postnatal growth, glucose tolerance, adiposity, or hypertension only emerged when PAE offspring were compared just against H2O controls, or against MD controls. We conclude that prior reports of obesity and glucose intolerance in adult PAE offspring reflect the contribution of added gestational calories, and not alcohol’s pharmacologic action. Results suggest that the increased adiposity risk in FASD is not caused by metabolic reprogramming, and instead originates from behavioral, medication, and/or dietary practices. This study highlights the importance of appropriate dietary controls in nutritional studies of PAE.

尽管产前酒精暴露（prenatal alcohol exposure, PAE）会对子代生长产生抑制作用，却可能提升青春期个体的肥胖风险。PAE的动物模型表现出葡萄糖耐受不良与脂肪堆积增加的特征，提示PAE可引发代谢重编程。我们在暴饮型产前酒精暴露（binge PAE）小鼠模型中验证了这一假说：妊娠第12.5天至17.5天期间，妊娠C57Bl/6J雌性小鼠每日接受3 g/kg酒精（ethanol, ETOH）灌胃；以麦芽糊精（maltodextrin, MD）和中链甘油三酯（medium chain triglycerides, MCT）作为等热量营养对照，并设置假处理（去离子水, H₂O）组以控制灌胃应激的影响。我们对17周龄子代小鼠开展了全面评估，量化其身体成分、能量消耗、葡萄糖耐受水平与心血管功能。尽管ETOH组幼崽初始体重低于其余所有组别，但并未表现出独特的致肥胖表型。相反，三个等热量组（MCT、MD、ETOH）均出现了相似的致肥胖表型：与假处理组子代相比，等热量组小鼠的断奶后体重增幅（雌雄均如此）更高，雄性小鼠的性腺脂肪重量更低，且雄性小鼠的葡萄糖清除率下降。PAE并未对子代的身体成分、呼吸交换比、高脂/低脂饮食下的代谢适应、进食行为与血压产生影响，且ETOH组的各项指标与等热量对照组并无显著差异。更高剂量酒精（4.5 g/kg）暴露或高脂（60%脂肪）饮食干预均未加剧身体成分或葡萄糖耐受方面的差异。仅当将PAE子代与假处理组或麦芽糊精对照组单独比较时，才会观察到“PAE特异性”的产后生长、葡萄糖耐受、脂肪堆积或高血压相关效应。我们得出结论：既往关于成年PAE子代出现肥胖与葡萄糖耐受不良的报道，实际反映的是妊娠期额外摄入热量的贡献，而非酒精的药理作用。研究结果提示，胎儿酒精谱系障碍（Fetal Alcohol Spectrum Disorder, FASD）患者的脂肪堆积风险升高并非源于代谢重编程，而是源自行为、药物干预和/或饮食方式的影响。本研究强调了在PAE相关营养研究中设置合理饮食对照的重要性。