The effect of maternal and postnatal obesity on offspring anxiety and memory and the role of altered HPA axis function and neuroinflammation

Abstract

Poor maternal nutrition during pregnancy is detrimental to fetal development and adversely affects long-term health by increasing the risk of chronic diseases, such as neuropsychiatric disorders. Previous studies show that maternal obesity may influence offspring behaviour such as anxiety/stress in adult life. This may be due to altered development of the hypothalamo-pituitaryadrenal (HPA) axis. This may be exacerbated by obesity in adult life which independently influences behaviour and HPA axis function. The mechanisms behind the effect of obesity to impact neuropsychiatric disorders is unclear, however increased inflammation found in obese individuals may be inducing permanent changes to HPA function. This study investigated the effects of maternal and postnatal obesity on behaviour, HPA axis function in young and mature adult mouse offspring, and assessed neuroinflammation as a potential mechanism.

In this study, female C57BL/6 mice were fed either an obesogenic high-fat diet (HF; 45% kcal fat) or control diet (C; 7% kcal fat) 6 weeks before mating, throughout pregnancy and lactation. Offspring were fed C or HF diet from weaning onwards. Maternal care and pup anxiety were assessed on postnatal day 7 via pup retrieval and ultrasonic vocalisations (USVs) during maternal separation. In 15 and 52 week-old offspring, anxiety was assessed by open field (OF) and elevated plus maze (EPM) and memory was assessed by novel object recognition (NOR). Corticosterone and ACTH concentrations (basal and area under curve [AUC]) were measured during a 30 minute restraint test. Analysis of neuroinflammation was performed via immunohistochemistry and mRNA levels of genes associated with HPA axis function and inflammation.

A maternal obesogenic HF diet was associated with poor maternal care and anxiety in males from 1 week of age, and subtle changes to anxiety persisted into young and mature adulthood. Postnatal obesity was associated with decreased and increased anxiety at 15 and 52 weeks of age respectively, and memory was impaired at 15 but not 52 weeks of age in males. Changes in anxiety and memory were associated with HPA dysregulation and microglial activation in the brain at 15 but not 52 weeks of age in males. In female offspring, changes in anxiety and memory were only observed at 52 weeks of age due to postnatal and maternal obesity respectively. Anxiety, but not memory, in females corresponded to changes in HPA regulation, but not inflammation at this age.

Maternal obesity, in addition to further postnatal obesity, subtly exacerbates some effects of anxiety and the stress response which is seen primarily in male, but not female, offspring at multiple ages. Overall, the effect of maternal obesity is sex-specific and age-dependent. These data are a novel addition to the existing literature on the effects of maternal obesity on HPA axis function and behaviour, particularly due to the additional assessment of further postnatal obesity. Further analysis of the role of inflammation during obesity at different stages of the life course will enhance our understanding of the risk of neuropsychiatric disorders to future generations.

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Identifiers

ORCID for Kirsten Poore: orcid.org/0000-0002-1455-0615

ORCID for Lucy Green: orcid.org/0000-0001-7423-9696

ORCID for Felino Cagampang: orcid.org/0000-0003-4404-9853

ORCID for Jessica Teeling: orcid.org/0000-0003-4004-7391

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