title: Neonatal overfeeding alters hypothalamic microglial profiles and central responses to immune challenge long-term.
abstract: The early life period is one of significant vulnerability to programming effects from the environment. Given the sensitivity of microglial cells to early life programming and to adult diet, we hypothesized overfeeding during the neonatal period would acutely alter microglial profiles within the developing brain, predisposing the individual to a lasting central pro-inflammatory profile that contributes to overactive immune responses long-term. We tested this idea by manipulating litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of 4 (neonatally overfed) or 12 (control). This manipulation induces obesity and susceptibility to lipopolysaccharide (LPS) long-term. We then examined microglial and central pro-inflammatory profiles during development and in adulthood as well as susceptibility to neuroimmune challenge with LPS. Neonatally overfed rats have evidence of microgliosis in the paraventricular nucleus of the hypothalamus (PVN) as early as postnatal day 14. They also show changes in hypothalamic gene expression at this time, with suppressed hypothalamic interleukin 1β mRNA. These effects persist into adulthood, with basal PVN microgliosis and increased hypothalamic toll-like receptor 4, nuclear factor κB, and interleukin 6 gene expression. These neonatally overfed rats also have dramatically exacerbated microglial activation in the PVN 24h after an adult LPS challenge, coupled with changes in inflammatory gene expression. Thus, it appears neonatal overfeeding sensitizes PVN microglia, contributing to a basal pro-inflammatory profile and an altered response to a neuroimmune challenge throughout life. It remains to be seen if these effects can be reversed with early interventions.
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Ilvana
authors: I
authors: Ziko
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Simone
authors: S
authors: De Luca
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Tara
authors: T
authors: Dinan
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Joanne M
authors: JM
authors: Barwood
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Luba
authors: L
authors: Sominsky
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Guohui
authors: G
authors: Cai
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Rachel
authors: R
authors: Kenny
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Leanne
authors: L
authors: Stokes
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia.
authors: Trisha A
authors: TA
authors: Jenkins
authors: School of Health Sciences and Health Innovations Research Institute (HIRi), Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia. Electronic address: Sarah.Spencer@rmit.edu.au.
authors: Sarah J
authors: SJ
authors: Spencer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007228:Infant Nutrition Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007231:Infant, Newborn; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008098:Litter Size; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D015213:Neuroimmunomodulation / Q000502:physiology; D050177:Overweight / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D010286:Paraventricular Hypothalamic Nucleus / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D016037:Single-Blind Method; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics; D015430:Weight Gain
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C433788:lipopolysaccharide, E. coli O26-B6
keywords: Interleukin 6 (IL-6); Ionized calcium-binding adapter molecule-1 (Iba-1); Lipopolysaccharide (LPS); Paraventricular nucleus of the hypothalamus (PVN); Toll-like receptor 4 (TLR4)