Metabolic consequences of stress during childhood and adolescence

Abstract

Stress, that is, the state of threatened or perceived as threatened homeostasis, is associated with activation of the stress system, mainly comprised by the hypothalamic-pituitary-adrenal axis and the arousal/sympathetic nervous systems. The stress system normally functions in a circadian manner and interacts with other systems to regulate a variety of behavioral, endocrine, metabolic, immune, and cardiovascular functions. However, the experience of acute intense physical or emotional stress, as well as of chronic stress, may lead to the development of or may exacerbate several psychologic and somatic conditions, including anxiety disorders, depression, obesity, and the metabolic syndrome. In chronically stressed individuals, both behavioral and neuroendocrine mechanisms promote obesity and metabolic abnormalities: unhealthy lifestyles in conjunction with dysregulation of the stress system and increased secretion of cortisol, catecholamines, and interleukin-6, with concurrently elevated insulin concentrations, lead to development of central obesity, insulin resistance, and the metabolic syndrome. Fetal life, childhood, and adolescence are particularly vulnerable periods of life to the effects of intense acute or chronic stress. Similarly, these life stages are crucial for the later development of behavioral, metabolic, and immune abnormalities. Developing brain structures and functions related to stress regulation, such as the amygdala, the hippocampus, and the mesocorticolimbic system, are more vulnerable to the effects of stress compared with mature structures in adults. Moreover, chronic alterations in cortisol secretion in children may affect the timing of puberty, final stature, and body composition, as well as cause early-onset obesity, metabolic syndrome, and type 2 diabetes mellitus. The understanding of stress mechanisms leading to metabolic abnormalities in early life may lead to more effective prevention and intervention strategies of obesity-related health problems.

Introduction

Childhood and adolescence are periods of continuous physical growth and emotional development, and great brain plasticity. Strong evidence has suggested that the experience of intense acute or chronic stress during these critical periods of life may have long-term and frequently irreversible effects on emotion; behavior; growth; metabolism; and reproductive, immune, and cardiovascular function [1], [2]. Both lifestyle and neuroendocrine mechanisms contribute to the development of metabolic and other alterations in stressed individuals [3]. Typically, but not necessarily, an obese phenotype mediates the effects of chronic stress on metabolism. This article summarizes the mechanisms and the effects of stress during fetal life, childhood, and adolescence, with emphasis on metabolic consequences. It provides also a review of the existing pediatric literature on the effects of physical and emotional stress in these crucial periods of human development.

Stress, the state of threatened or perceived as threatened homeostasis, is associated with activation of the stress system, which is located in the central nervous system and the periphery of the organism. The stress system consists mainly of 2 axes, the hypothalamic corticotropin-releasing hormone (CRH) system, regulating the hypothalamic-pituitary-adrenal (HPA) axis and the brainstem locus caeruleus/norepinephrine (LC/NE) system, regulating arousal and autonomic (sympathetic) nervous system function [4], [5], [6]. Centrally, the main mediators of the stress system are the hypothalamic paraventricular nucleus hormones CRH and arginine vasopressin, the arcuate nucleus proopiomelanocortin-derived peptides α-melanocyte–stimulating hormone and β-endorphin, and the brainstem NE produced in the A1/A2 centers of the LC and the central nuclei of the sympathetic nervous system (SNS). In the periphery, the end-effectors of the HPA axis are the glucocorticoids; and those of the sympathetic system are the catecholamines epinephrine and NE [4], [5], [6]. In addition to the main components and mediators of the stress system, other systems and their mediators, which can be neurotransmitters, hormones, cytokines, and growth factors, interact with them to further regulate and fine-tune homeostasis. The targets of all these stress and related mediators are brain structures with functions related to emotion and behavior, as well as central nervous system and peripheral tissues related to growth, metabolism, reproduction, immunity, and cardiovascular function.

In normal conditions, activation of the stress system caused by everyday stressors results in adaptive endocrine, metabolic, and cardiovascular changes that help maintain homeostasis [7]. However, the experience of intense real or perceived stressors, such as accidents, natural disasters, war or terrorism, physical or sexual abuse, bereavement, etc, can lead to excessive and prolonged activation of the stress system or, in a subgroup of individuals, to chronic hypoactivation of this system, with a variety of psychologic and biological consequences [4], [5], [6], [7].

Chronic hypersecretion of stress hormones, as evidenced by elevated cortisol and catecholamine concentrations in the circulation, results in insulin hypersecretion and growth and sex steroid hormone hyposecretion. These effects lead to long-term accumulation of fat especially in visceral adipose tissue, loss of muscle (sarcopenia), and osteoporosis with adverse clinical and metabolic consequences, including arterial hypertension, carbohydrate intolerance, dyslipidemia (metabolic syndrome), and type 2 diabetes mellitus [4], [5], [8], [9].

Glucocorticoids, secreted by the adrenal cortices, together with the autonomic nervous system, play a crucial role in the stress response, altering target tissue activities and shifting metabolism toward catabolism [9], [10], [11], [12], [13]. Circulating cortisol in humans has a circadian pattern of secretion regulated by the suprachiasmatic nucleus of the hypothalamus [14]. The zenith of cortisol concentrations is reached in the early morning; and the nadir, at midnight. Recent data have shown that the circadian rhythm transcription factor Clock acetylates the glucocorticoid receptor (GR) and represses GR-induced transcriptional activity of several glucocorticoid-responsive genes [15]. Clock and its heterodimer partner brain muscle ARNT-like protein 1 play an essential role in the formation of the circadian rhythm of central and peripheral systems. Furthermore, the peripheral Clock regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man [16]. The effects of this system on the sensitivity of target tissues to cortisol suggest that even mild dysregulation of stress system activity, such as the chronic slight evening elevations of cortisol associated with chronic stress, in conjunction with the elevated evening sensitivity to glucocorticoids, may explain the development of central obesity and consequent metabolic alterations in chronically stressed individuals [14], [15], [16], [17].