Overfeeding during a critical postnatal period exacerbates hypothalamic-pituitary-adrenal axis responses to immune challenge: a role for adrenal melanocortin 2 receptors

Abstract

Early life diet can critically program hypothalamic-pituitary-adrenal (HPA) axis function. We have previously shown rats that are overfed as neonates have exacerbated pro-inflammatory responses to immune challenge with lipopolysaccharide (LPS), in part by altering HPA axis responses, but how this occurs is unknown. Here we examined neonatal overfeeding-induced changes in gene expression in each step of the HPA axis. We saw no differences in glucocorticoid or mineralocorticoid receptor expression in key regions responsible for glucocorticoid negative feedback to the brain and no differences in expression of key HPA axis regulatory genes in the paraventricular nucleus of the hypothalamus or pituitary. On the other hand, expression of the adrenal melanocortin 2 receptor (MC2R) is elevated after LPS in control rats, but significantly less so in the neonatally overfed. The in vitro adrenal response to ACTH is also dampened in these rats, while the in vivo response to ACTH does not resolve as efficiently as it does in controls. These data suggest neonatal diet affects the efficiency of the adrenally-mediated response to LPS, potentially influencing how neonatally overfed rats combat bacterial infection.

Neonatal overfeeding by small‐litter rearing sensitises hippocampal microglial responses to immune challenge: Reversal with neonatal repeated injections of saline or minocycline

“…However, stressful stimuli can sensitise central pro-inflammatory responses and the activation of microglia.To determine whether the repeated neonatal injections effects on microglia were associated with long-term changes to the HPA axis, we measured basal circulating corticosterone in neonatally non-injected and injected (saline) adult rats. The findings of the present study are consistent with previous studies from our group showing that corticosterone levels in non-injected neonatally overfed rats are not significantly different from non-injected control-fed rats 2,15,33. Surprisingly, we found that the neonatally overfed animals undergoing repeated neonatal injections had significantly increased basal corticosterone levels compared to the non-injected equivalent and this difference was not seen in the neonatally injected control-fed animals.…”

“…We have previously shown that this manipulation results in the neonatally overfed pups being significantly heavier by P7 and throughout life . We have previously reported weight data from this cohort of rats and have analysed their HPA axis responses to an immune challenge …”

“…2,5,11,15 We have previously reported weight data from this cohort of rats and have analysed their HPA axis responses to an immune challenge. 33 At P0, control-fed and neonatally overfed pups were allocated to either a 3-week treatment regimen or were untreated, except for the litter size manipulation, until experimentation in adulthood; approximately P70 (Figure 1). For the neonatal treatment, we administered either minocycline (22.5 mg kg -1 i.p.…”

The initiation of metabolic inflammation in childhood obesity

“…Postnatal overfeeding (PNOF) in rats is sufficient to induce hypothalamic inflammation and gliosis as early as postnatal day 14 and leads to a persistent increase in hypothalamic NF-κB activity in adulthood (61,62). PNOF can enhance microglial activation in response to HFD in adults, which suggests that the inflammatory set point in the brain is permanently modified with accelerated early life growth (63,64). The mechanism of the persistent alterations in hypothalamic inflammation with PNOF may be different than HFD-induced hypothalamic inflammation in adult mice, which is reversible (18,65).…”

Obesity after neonatal overfeeding is independent of hypothalamic microgliosis

“…Similarly, rats that were overfed as neonates have exacerbated febrile, anorexigenic and neuroimmune responses to immune challenge with bacterial mimetic lipopolysaccharide (LPS) . Associated with these long‐term effects is brain‐wide microglia with a “primed” phenotype (ie, increased microglial numbers and activated morphology without an increase in pro‐inflammatory cytokine expression under basal conditions) . These microglia hyper‐respond to an immune challenge by proliferating to a greater degree in the paraventricular nucleus of the hypothalamus (PVN), arcuate nucleus (ARC) and hippocampus 24 hours after LPS compared to normally fed controls .…”