Developmental programming of Kupffer cells by maternal obesity causes fatty liver disease in the offspring

Kupffer cells (KCs) are tissue-resident macrophages which colonize the liver early during embryogenesis. KCs start to acquire a tissue-specific transcriptional signature immediately after colonizing the liver, mature together with the tissue, and adapt to the tissue?s functions. Throughout development and adulthood, KCs have distinct core functions that are essential for liver and organismal homeostasis, such as supporting fetal erythropoiesis as well as postnatal erythrocyte recycling and liver metabolism. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs mediate lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonates born to obese mothers, followed by replenishment with exogenous monocytes, rescues the fatty liver disease. The transcriptional programming of KCs and the fatty liver disease phenotype are also rescued by genetic depletion of hypoxia-inducible factor alpha (Hif1?) in macrophages during gestation. These results establish developmental perturbation of KC functions as a cause for the development of fatty liver disease in adult life and, thereby, place fetal-derived macrophages as intergenerational messengers within the concept of developmental origins of health and diseases.

库普弗细胞（Kupffer cells，KCs）是一类组织驻留巨噬细胞，于胚胎发生早期定植于肝脏。KCs在定植肝脏后即刻获得组织特异性转录特征，随肝脏组织同步成熟并适配其生理功能。在个体发育及成年阶段，KCs发挥独特的核心功能，对维持肝脏与机体稳态至关重要，例如支持胎儿红细胞生成、产后红细胞回收及肝脏代谢。然而，发育过程中巨噬细胞核心功能的扰动是否会在产后阶段诱发或导致疾病，目前尚不清楚。本研究利用母体肥胖小鼠模型，在妊娠期扰动KCs的功能。研究发现，暴露于母体肥胖环境的子代小鼠会发生脂肪性肝病，该表型由持续至成年的KCs异常发育编程所驱动。经编程的KCs通过分泌载脂蛋白介导肝细胞的脂质摄取。对肥胖母鼠所产新生小鼠进行KCs耗竭，并以外源性单核细胞进行重建后，可挽救该脂肪性肝病表型。妊娠期在巨噬细胞中特异性敲除缺氧诱导因子α（hypoxia-inducible factor alpha，HIF1α），同样可挽救KCs的转录编程异常及脂肪性肝病表型。上述结果证实，发育过程中KCs功能的扰动是成年期脂肪性肝病的致病诱因之一，从而将胎儿来源的巨噬细胞确立为健康与疾病发育起源理论中的代间信使。