Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

早期生活决定因素被认为是肥胖迅速增加的主要因素。然而，虽然对母体营养进行了广泛研究，但婴儿母乳喂养对儿童期和整个成年期能量平衡重新编程的影响仍然很大程度上未知。在这里，我们表明，通过增强棕色脂肪组织产热和能量消耗，大鼠幼崽延迟断奶可以保护它们免受成年期饮食引起的肥胖。在该大鼠模型和转基因小鼠中进行的深入代谢表型分析表明，长时间哺乳的影响是由成年期肝成纤维细胞生长因子 21 (FGF21) 产生增加和 tanycyte 控制进入下丘脑介导的。具体来说，FGF21 激活在下丘脑外侧区和无定带中表达多巴胺受体 2 的含 GABA 神经元。因此，长期母乳喂养通过影响肝脏与下丘脑通讯和下丘脑代谢调节的长期生理变化，构成了一种针对肥胖的保护机制。