Early-Life Stress, HPA Axis Adaptation, and Mechanisms Contributing to Later Health Outcomes

Abstract

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which then modulates the degree of adaptation and response to a later stressor. It is known that early-life stress can impact on later health but less is known about how early-life stress impairs HPA axis activity, contributing to maladaptation of the stress-response system. Early-life stress exposure (either prenatally or in the early postnatal period) can impact developmental pathways resulting in lasting structural and regulatory changes that predispose to adulthood disease. Epidemiological, clinical, and experimental studies have demonstrated that early-life stress produces long term hyper-responsiveness to stress with exaggerated circulating glucocorticoids, and enhanced anxiety and depression-like behaviors. Recently, evidence has emerged on early-life stress-induced metabolic derangements, for example hyperinsulinemia and altered insulin sensitivity on exposure to a high energy diet later in life. This draws our attention to the contribution of later environment to disease vulnerability. Early-life stress can alter the expression of genes in peripheral tissues, such as the glucocorticoid receptor and 11-beta hydroxysteroid dehydrogenase (11β-HSD1). We propose that interactions between altered HPA axis activity and liver 11β-HSD1 modulates both tissue and circulating glucocorticoid availability, with adverse metabolic consequences. This review discusses the potential mechanisms underlying early-life stress-induced maladaptation of the HPA axis, and its subsequent effects on energy utilization and expenditure. The effects of positive later environments as a means of ameliorating early-life stress-induced health deficits, and proposed mechanisms underpinning the interaction between early-life stress and subsequent detrimental environmental exposures on metabolic risk will be outlined. Limitations in current methodology linking early-life stress and later health outcomes will also be addressed.

Keywords: 11-beta hydroxysteroid dehydrogenase 1; early-life stress; glucocorticoids; hyperinsulinemia; insulin signaling; liver; metabolic disorders.

Figure 1

How does ELS increase the risk for insulin resistance and hyperglycemia? Early-life stress (ELS) induced by three different paradigms including maternal deprivation, maternal separation, and limited nesting material are known to dysregulate HPA axis activity, with limited data on the effects of ELS on hypothalamic feeding neuropeptides and inflammation. It is proposed that ELS disturbs circulating glucocorticoids (GC) through a combined action of HPA axis activity, hypothalamic feeding neuropeptides, and inflammatory changes. The effects of ELS on liver 11β-HSD1, an enzyme that converts inactive GC to active GC, and 5α-reductase, an enzyme involved in GC metabolism, is less known. It is proposed that during the maladaptation period, ELS affects tissue levels of these enzymes, thus increasing exposure of peripheral tissues to GC. Excess GC availability can alter insulin signaling, leading to hyperinsulinemia and insulin resistance over time. Thus, increases in circulating and tissue GC induced by ELS act synergistically to exacerbate insulin resistance in peripheral tissues and alter energy expenditure and utilization. ELS, early-life stress; MD, maternal deprivation; MS, maternal separation; LN, limited nesting material; GC, glucocorticoids; TNF-α, tumor necrosis factor alpha; IL-6, interleukin 6; IL-1β, interleukin-1 beta; 11β-HSD1, 11-beta hydroxysteroid dehydrogenase.

Figure 2

The combination of early-life stress exposure with altered later environment may determine metabolic outcomes. Early-life stress (ELS) exposure during gestation or the postnatal period is hypothesized to influence an offspring’s response to later environments (85, 87). This programing occurs in an attempt to facilitate habituation and resilience to future similar situations. Offspring exposed to environments that do not differ to that to which they were exposed during early life, i.e., “matched” or positive environments, such as exposure to exercise have been shown to adapt and demonstrate resilience (74, 114, 131, 132). Conversely, exposure to a negative environment, i.e., “mismatched,” such as a sub-optimal diet (131, 132, 134) or chronic stress following ELS may lead to maladaptation, and metabolic deficits, with increased levels of triglycerides, free fatty acids, adiposity, and insulin resistance as measured by HOMA-IR. Thus, there is a pendulum of vulnerability and the trajectory following ELS is influenced by the later life environment.