Priming of Hypothalamic Ghrelin Signaling and Microglia Activation Exacerbate Feeding in Rats’ Offspring Following Maternal Overnutrition

Abstract

Maternal overnutrition during pregnancy leads to metabolic alterations, including obesity, hyperphagia, and inflammation in the offspring. Nutritional priming of central inflammation and its role in ghrelin sensitivity during fed and fasted states have not been analyzed. The current study aims to identify the effect of maternal programming on microglia activation and ghrelin-induced activation of hypothalamic neurons leading to food intake response. We employed a nutritional programming model exposing female Wistar rats to a cafeteria diet (CAF) from pre-pregnancy to weaning. Food intake in male offspring was determined daily after fasting and subcutaneous injection of ghrelin. Hypothalamic ghrelin sensitivity and microglia activation was evaluated using immunodetection for Iba-1 and c-Fos markers, and Western blot for TBK1 signaling. Release of TNF-alpha, IL-6, and IL-1β after stimulation with palmitic, oleic, linoleic acid, or C6 ceramide in primary microglia culture were quantified using ELISA. We found that programmed offspring by CAF diet exhibits overfeeding after fasting and peripheral ghrelin administration, which correlates with an increase in the hypothalamic Iba-1 microglia marker and c-Fos cell activation. Additionally, in contrast to oleic, linoleic, or C6 ceramide stimulation in primary microglia culture, stimulation with palmitic acid for 24 h promotes TNF-alpha, IL-6, and IL-1β release and TBK1 activation. Notably, intracerebroventricular (i.c.v.) palmitic acid or LPS inoculation for five days promotes daily increase in food intake and food consumption after ghrelin administration. Finally, we found that i.c.v. palmitic acid substantially activates hypothalamic Iba-1 microglia marker and c-Fos. Together, our results suggest that maternal nutritional programing primes ghrelin sensitivity and microglia activation, which potentially might mirror hypothalamic administration of the saturated palmitic acid.

Potential role of primed microglia during obesity on the mesocorticolimbic circuit in autism spectrum disorder

“…On this context, recent reports have identified that fetal brain microglia from obese mothers displays a pro-inflammatory cytokine in response to immune LPS challenge (Edlow et al, 2019), a similar pattern of response was identified in glucose-deprived microglial cells, a pathological state included in diabetes (Churchward, Tchir, & Todd, 2018). We also reported that primed microglia from mothers programmed by exposure to western diet display major active profile followed by intrahypothalamic LPS administration (Maldonado-Ruiz, Cárdenas-Tueme, et al, 2019). In fact, microglial depletion still shows a pro-inflammatory and molecular signatures of aged microglia (O'Neil, Witcher, McKim, & Godbout, 2018) and shows hyperactivity after repopulation (Weber et al, 2019), suggesting that primed microglia conserve their original molecular sig- Table 2).…”

“…Mice exposed to maternal hypercaloric diet during pregnancy have confirmed microglial priming (Banik et al, 2017;Maldonado-Ruiz, Cárdenas-Tueme, et al, 2019) and defective mesocorticolimbic activity to a natural reward and depression-like behaviour in the offspring (Camacho, Montalvo-Martinez, Cardenas-Perez, Fuentes-Mera, & Garza-Ocañas, 2017;de la Garza et al, 2019;Naef et al, 2011).…”

Microglial and peripheral immune priming is partially sexually dimorphic in adolescent mouse offspring exposed to maternal high-fat diet

“…Bilbo and Tsang previously reported higher density of IBA1 + cells in the hippocampus CA1, CA3, and dentate gyrus of mHFD-exposed male and female rat offspring at adulthood [ 8 ]. Similar effect of IBA1 + increase has also been recently reported in the hypothalamus of rat offspring exposed to a maternal overnutrition model (high-sugar-fat) [ 45 ]. In the present study, we did not observe any change in microglial density in the st rad and st lac mol of the dorsal hippocampus CA1.…”

“…Microglial cell density, distribution, gene expression signature, physiological functions, and/or response to immune challenges may be altered upon exposure to various environmental factors, thus impacting on their sculpting of the brain network [ 43 , 44 ]. This phenomenon is referred to as immune priming [ 43 – 45 ]. Studying microglial priming during sensitive periods like adolescence, in which the brain and especially the hippocampus experience important synaptic changes, may help to understand the pathological cascade underlying mHFD.…”

Maternal cafeteria diet exposure primes depression-like behavior in the offspring evoking lower brain volume related to changes in synaptic terminals and gliosis

“…Conversely, studies in depressed post mortem patients 63 and animal models of chronic stress reported a time-dependent reduction in glial cell number in the CA1 of hippocampus, potentially owing to a selective neuroadaptive response to stress 20 . Also, glial alterations in MDD might presumably be related to active release of S100B by astrocytes 64 or microglia activation during programming 65 . Hippocampal shrinkage may be explained by a decrease in glial cells number and/or loss in the number of neurons due to a neurotoxic effect of glucocorticoids 66 , which are increased in depressed patients 4 , 67 , and have been found in murine models exposed to perinatal high-fat diet 68 .…”