Elsevier

Neuroscience

Volume 240, 14 June 2013, Pages 1-12
Neuroscience

Perinatal high fat diet alters glucocorticoid signaling and anxiety behavior in adulthood

https://doi.org/10.1016/j.neuroscience.2013.02.044Get rights and content

Abstract

Maternal obesity carries significant health risks for offspring that manifest later in life, including metabolic syndrome, cardiovascular disease and affective disorders. Programming of the hypothalamic–pituitary–adrenal (HPA) axis during development mediates both metabolic homeostasis and the response to psychosocial stress in offspring. A diet high in fat alters maternal systemic corticosterone levels, but effects in offspring on limbic brain areas regulating the HPA axis and anxiety behavior are poorly understood. In addition to their role in the response to psychosocial stress, corticosteroid receptors form part of the glucocorticoid signaling pathway comprising downstream inflammatory processes. Increased systemic inflammation is a hallmark of high-fat diet exposure, though altered expression of these genes in limbic brain areas has not been examined. We studied the influence of high-fat diet exposure during pre-weaning development in rats on gene expression in the amygdala and hippocampus by quantitative real-time polymerase chain reaction (PCR), anxiety behavior in the Open field, elevated plus maze and light–dark transition tasks, and corticosterone levels in response to stress by radioimmunoassay. As adults, offspring exposed to perinatal high-fat diet show increased expression of corticosterone receptors in the amygdala and altered pro-inflammatory and anti-inflammatory expression in the hippocampus and amygdala in genes known to be regulated by the glucocorticoid receptor. These changes were associated with increased anxiety behavior, decreased basal corticosterone levels and a slower return to baseline levels following a stress challenge. The data indicate that the dietary environment during development programs glucocorticoid signaling pathways in limbic areas relevant for the regulation of HPA function and anxiety behavior.

Highlights

► Perinatal high-fat diet increases anxiety and alters corticosteroid levels. ► Perinatal high-fat diet increases corticosteroid receptor expression in amygdala. ► Perinatal high-fat diet alters limbic pro- and anti-inflammatory gene expression. ► Glucocorticoid signaling in response to high-fat diet is sexually dimorphic.

Introduction

Obesity is increasingly common during pregnancy, exposing the developing child to significant health risks (King, 2006). The overconsumption of saturated fat is most closely linked with deleterious health effects on offspring development (Bersamin et al., 2008). Exposure to a diet high in fat during development is a well known risk factor for coronary heart disease, type 2 diabetes and the metabolic syndrome in adulthood (Marx, 2002, Boksa, 2004, Kahn et al., 2006, Van Gaal et al., 2006, Peleg-Raibstein et al., 2012). In addition, obesity increases the risk of behavioral disorders associated with anxiety in humans, effects that are particularly pronounced among females (Desai et al., 2009, Rofey et al., 2009).

Animal models of diet-induced obesity have been important tools for understanding the influence of overnutrition on metabolic development (Bouret, 2009). For example, maternal diets high in saturated fats and refined sugar compared to standard chow impact gene expression in brain reward systems and alter offspring food preferences for fat-rich foods (Ong and Muhlhausler, 2011). Few studies to date have examined the influence of perinatal high-fat diet on the development of neural systems mediating anxiety behavior. The results of studies of the role of perinatal high-fat diet on both basal and stress-challenged levels of circulating corticosterone in adult offspring have been unclear due to conflicting findings (Walker et al., 2008, Auvinen et al., 2011). Non-human primates developmentally exposed to a high-fat diet show increased fear responses in the presence of novelty (Sullivan et al., 2010) and in rodents high-fat diet exposure during development appears to increase anxiety behavior in the Open field and Elevated plus maze tasks (Bilbo and Tsang, 2010, Peleg-Raibstein et al., 2012). To date, the impact of high-fat diet exposure during perinatal development on brain-region specific changes associated with increased anxiety behavior remains poorly understood.

Many studies in animal models have demonstrated that environmental factors during perinatal development have a long-term impact on the function of the hypothalamic–pituitary–adrenal (HPA) axis, a primary mediator of the endocrine response to stress. For example, maternal stress during pregnancy or maternal care in early postnatal life have long-term effects on anxiety behavior in offspring and the expression of genes in the brain critical for the function of the HPA axis (Meaney, 2001, Welberg and Seckl, 2001, McGowan et al., 2008, Brunton, 2010). These factors are known to alter HPA function in offspring in part via changes in the expression of mineralocorticoid and glucocorticoid receptors in limbic brain areas, including the amygdala and hippocampus, that regulate basal and stress-activated levels of corticosterone in circulation (Welberg and Seckl, 2001, Brunton, 2010). There is also increasing recognition of the role of glucocorticoid receptors in the regulation of downstream inflammatory processes as a result of altered HPA function (Sorrells et al., 2009).

Obesity has long been known to induce markers of inflammation in the body (Bray et al., 2002). Recent data in animal models suggest that high-fat diet exposure changes glial activation of inflammatory processes in the hypothalamus and in the hippocampus (Bilbo and Tsang, 2010, Peleg-Raibstein et al., 2012). In the hypothalamus, pro-inflammatory cytokines including NFkB, IL-6 and other downstream signaling molecules including IKB represent the largest class of genes with altered expression as a function of chronic high-fat diet consumption (De Souza et al., 2005, Velloso et al., 2008, Thaler and Schwartz, 2010). However, to our knowledge, the influence of developmental exposure to high-fat diet on the expression of these inflammatory genes in the amygdala, a brain area long known to be critically involved in anxiety behavior (Davis, 1992), has not been studied.

Here, we examine the impact of perinatal high-fat diet exposure on corticosteroid receptor and downstream pro- and anti-inflammatory gene expression in limbic brain areas important for the response to psychosocial stress and anxiety behavior in adulthood, two components of the adaptive response system mediated by the HPA axis.

Section snippets

Animals

Adult male and female Long Evans rats (7 week) used were obtained from Charles River Canada (St. Constant, QC), housed in same-sex pairs and maintained on a 12:12-h light–dark cycle (lights on 7:00 am–7:00 pm) with ad libitum access to food and water. Experimental protocols were approved by the Local Animal Care Committee at the University of Toronto, Scarborough, and were in accordance with the guidelines of the Canadian Council on Animal Care.

Diets

Female breeders were placed on one of two diets: a

Maternal body weight and caloric intake

To ensure adequate exposure to high-fat diet, dams were given ad libitum access to high-fat diet or control chow diet for 4 weeks prior to pregnancy and throughout gestation and lactation. Dams consuming high-fat diet gained significantly more weight than chow-fed dams [F(1, 56) = 22.97, P < 0.01; Fig. 1A]. In addition, the high fat-fed dams’ average caloric intake during the last week prior to birth was significantly higher than that of chow-fed dams [t(1, 14) = 3.05, P < 0.01; Fig. 1B].

Offspring body weight

We next

Discussion

To our knowledge, this is the first study to examine changes in glucocorticoid signaling in response to perinatal high-fat diet exposure in limbic areas known to regulate HPA function and anxiety behavior. The results indicate that altered expression of corticosteroid receptors and inflammatory genes in the brain of adult offspring as a function of high-fat diet exposure during the perinatal period alone may contribute to a heightened endocrine response to stress and increased anxiety behavior

Acknowledgments

This work was supported by a New Researcher Award from the Connaught Fund and an operating grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) to P.O.M.

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