Microglia are required for developmental specification of AgRP innervation in the hypothalamus of offspring exposed to maternal high-fat diet during lactation.

Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus respond to multiple metabolic signals and distribute neuroendocrine information to other brain regions such as the paraventricular hypothalamic nucleus (PVH), which plays a central role in metabolic homeostasis. Neural projections from AgRP neurons to the PVH form during the postnatal lactational period in mice and these projections are reduced in offspring of dams that consumed a high-fat diet (HFD) during lactation (MHFD-L). Here, we used immunohistochemistry to visualize microglial morphology in MHFD-L offspring and identified changes that were regionally localized to the PVH and appeared temporally restricted to the period when AgRP neurons innervate this region. In addition, axon labeling experiments revealed that microglia engulf AgRP terminals in the PVH, and that the density of AgRP innervation to the PVH in MHFD-L offspring may be dependent on microglia, because microglial depletion blocked the decrease in PVH AgRP innervation observed in MHFD-L offspring, as well as prevented the increased body weight exhibited at weaning. Together, these findings suggest that microglia are activated by exposure to MHFD-L and interact directly with AgRP axons during postnatal development to permanently alter innervation of the PVH, with implications for developmental programming of metabolic phenotype.