Endogenous amylin contributes to birth of microglial cells in arcuate nucleus of hypothalamus and area postrema during fetal development

Abstract

Amylin acts in the area postrema (AP) and arcuate nucleus (ARC) to control food intake. Amylin also increases axonal fiber outgrowth from the AP→nucleus tractus solitarius and from ARC→hypothalamic paraventricular nucleus. More recently, exogenous amylin infusion for 4 wk was shown to increase neurogenesis in adult rats in the AP. Furthermore, amylin has been shown to enhance leptin signaling in the ARC and ventromedial nucleus of the hypothalamus (VMN). Thus, we hypothesized that endogenous amylin could be a critical factor in regulating cell birth in the ARC and AP and that amylin could also be involved in the birth of leptin-sensitive neurons. Amylin+/− dams were injected with BrdU at embryonic day 12 and at postnatal day 2; BrdU+ cells were quantified in wild-type (WT) and amylin knockout (KO) mice. The number of BrdU+HuC/D+ neurons was similar in ARC and AP, but the number of BrdU+Iba1+ microglia was significantly decreased in both nuclei. Five-week-old WT and KO littermates were injected with leptin to test whether amylin is involved in the birth of leptin-sensitive neurons. Although there was no difference in the number of BrdU+c-Fos+ neurons in the ARC and dorsomedial nucleus, an increase in BrdU+c-Fos+ neurons was seen in VMN and lateral hypothalamus (LH) in amylin KO mice. In conclusion, these data suggest that during fetal development, endogenous amylin favors the birth of microglial cells in the ARC and AP and that it decreases the birth of leptin-sensitive neurons in the VMN and LH.

Amylin and Leptin interaction: Role During Pregnancy, Lactation and Neonatal Development

“…Interestingly, among the cells being born, the same number of neurons was found in WT and KO, however less microglial cells were born in KO mice compared to WT. Meanwhile in the VMN, DMN, LH and AP, the number of newly born cells was similar in WT and KO, but, among those cells, less microglia cells were born in the AP of KO mice (Lutz and Le Foll, 2019). Thus, during brain development between day E12 and P2, amylin does not appear to play a role in neurogenesis processes, but it contributes to the birth and the fate of microglial cells in the ARC and AP.…”

“…We recently investigated the role of endogenous amylin during embryonic development (Lutz and Le Foll, 2019). Pregnant amylin KO and WT littermate mice were injected with BrdU, a thymidine analog and marker of newly born cells, at E11.5-E12, i.e.…”

Neurodevelopmental Programming of Adiposity: Contributions to Obesity Risk

“…During gestation, amylin is initially detected in pancreatic islet β-cells at E12 and peaks at E17 ( 282 , 283 ); the amylin receptor, CTR, is expressed in the brain starting at E12-13. Amylin knockout mice have fewer microglial cells in the ARH and AP at E12; neuronal numbers are unchanged ( 284 ). Postnatal neurotrophic effects of amylin have also been reported using RAMP 1/3 knockout mice and knock down of CTR in brains of P4 rats (both of which result in reduced amylin receptor signaling) and amylin KO mice, all showing reduced α-MSH fiber projections from ARH to PVH.…”

Microglia mediate the early-life programming of adult glucose control

“…Neuronal circuit development entails the formation, maturation, and stabilization of synapses, which consist of presynaptic and postsynaptic elements, the surrounding extracellular matrix (ECM), and glia including microglia. The peptide hormone amylin, which influences neurogenesis, axonal fiber outgrowth, and leptin signaling in the hypothalamus (20)(21)(22), also enables the birth of microglia in the ARC (23), suggesting that the emergence of hypothalamic microglia is co-regulated along with hypothalamic circuit development during embryogenesis and early postnatal life. Moreover, depleting fetal microglia, specifically during gestation using the CSF1R inhibitor PLX5622, reduces the number of postnatal POMC neurons in the MBH in association with accelerated weight gain starting at P5 (24).…”