Energetic stress: The reciprocal relationship between energy availability and the stress response

Abstract

The worldwide epidemic of metabolic syndromes and the recognized burden of mental health disorders have driven increased research into the relationship between the two. A maladaptive stress response is implicated in both mental health disorders and metabolic disorders, implicating the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of this relationship. This review explores how an altered energetic state, such as hyper- or hypoglycemia, as may be manifested in obesity or diabetes, affects the stress response and the HPA axis in particular. We propose that changes in energetic state or energetic demands can result in "energetic stress" that can, if prolonged, lead to a dysfunctional stress response. In this review, we summarize the role of the hypothalamus in modulating energy homeostasis and then briefly discuss the relationship between metabolism and stress-induced activation of the HPA axis. Next, we examine seven mechanisms whereby energetic stress interacts with neuroendocrine stress response systems, including by glucocorticoid signaling both within and beyond the HPA axis; by nutrient-induced changes in glucocorticoid signaling; by impacting the sympathetic nervous system; through changes in other neuroendocrine factors; by inducing inflammatory changes; and by altering the gut-brain axis. Recognizing these effects of energetic stress can drive novel therapies and prevention strategies for mental health disorders, including dietary intervention, probiotics, and even fecal transplant.

Keywords: Glucocorticoid; HPA axis; Metabolic dysfunction; Obesity; Stress.

Figure 1. Disruptions to Energy homeostasis Alter the Stress Response through Multiple Mechanisms

States of disrupted energy availability, such as hypoglycemia or obesity, can result in an impaired stress response in seven key areas. A dysfunctional response to the neuroendocrine stimulus to feed (1) may result states of energetic stress such as obesity or hypoglycemia (2), which further drives changes in the gut-brain axis (3), hypothalamic-pituitary-adrenal (HPA) axis activity (4), and sympathetic nervous system (SNS) drive (5). HPA axis SNS activity alters activity of glucocorticoids in adipose tissue (6), which feeds back to regulate feeding drive. In addition, both the HPA axis and gut-brain axis influence the immune system (7), which further alters stress reactivity and metabolic drive. Interactions among each of these elements are bidirectional and further clarified in Table 1.