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 developing liver early during embryogenesis¹. 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 metabolism². KCs start to acquire their tissue-specific transcriptional signature immediately after colonizing the liver, mature together with the tissue, and adapt to the tissue’s function^1,3,4. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a maternal obesity model to perturb KC functions during gestation. We show that mice experiencing maternal obesity during gestation develop fatty liver disease that is accompanied by a local inflammatory response. Transcriptional analyses reveal that KCs undergo developmental programming through maternal obesity, which persists in adulthood. The offspring’s KC developmental programming is irreversible and leads to increased lipid uptake in hepatocytes mediated via KCs. The transcriptional programming of KCs and the fatty liver disease phenotype are rescued by genetic depletion of hypoxia-inducible factor alpha (Hif1α) 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 diseases⁵.