The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances

Abstract

The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.

Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress

“…We saw clear differences in baseline glucose levels in both our MD groups. We initially hypothesized that this was a function of the altered HPA axis (106). However, it would appear that changes in the external environment did not induce changes in the HPA axis stress response nor in the overall glucocorticoid levels.…”

Adult Health and Early Life Adversity: Behind the Curtains of Maternal Care Research

“…Moreover, the epigenetics of aging are shown to be altered in the offspring of mothers who themselves experienced childhood trauma ( Nwanaji-Enwerem et al, 2021 ), solidifying a biological basis for transgenerational effects on the aging process. This lifespan approach to understanding maternal care and early life adversity has been validated numerous times and extended to circadian clocks, including the diurnal cortisol rhythm ( Cagampang et al, 2011 ), and systemic diseases, such as cardiovascular disease, diabetes, and metabolic syndrome ( Weaver, 2009 ; Seal and Turner, 2021 ).…”

Sex Dimorphic Responses of the Hypothalamus-Pituitary-Thyroid Axis to Energy Demands and Stress

“…Stress is another important player; acute stress activates the sympathetic nervous system and the HPA axis that mobilize energy substrates by stimulating lipolysis in WAT and increase the circulating concentration of glucose ( 131 ). Chronic stress in contrast promotes the accumulation of fat specially in the visceral region by the local activation of glucocorticoids (GC) induced by 11β-hydroxysteroid dehydrogenase-1, favoring hypertrophy of the adipocytes and altering responses of the HPA axis to subsequent stressors ( 131 , 132 ). Responses to stress are sex-dimorphic; adult female rodents have higher serum corticosterone concentration in basal condition or after acute stress exposure than males; this difference is attributed to a stimulatory effect of estrogens at all levels of HPA axis, and to a slower feedback inhibition due to a lower expression of glucocorticoid receptor (GR) in PVN and pituitary in females than males; androgens in turn, inhibit HPA axis activity at different levels ( 133 ).…”