MetS is a cluster of interconnected factors that directly increase the risk of cardiovascular atherosclerotic diseases, and diabetes mellitus type 2. Visceral obesity/insulin resistance have gained increasing attention as the core manifestations of the syndrome. HPA axis is one of the main stress response pathways. Apart from having a circadian activity also mediates the adaptive response to stressors. A growing body of evidence point towards a strong relationship between perturbations of HPA axis and metabolic syndrome.
Persistent over-stimulation of HPA axis by various stressors resulting to elevated circulating glucocorticoids can lead to metabolic syndrome components. Cortisol has been causally demonstrating to promote the accumulation of visceral adipose cells and visceral obesity. Moreover, acting through various pathways it increases the apetite, stimulates gluconeogenesis, glycogenolysis, lipolysis in subcutaneous fat tissue and over time causes insulin resistance, diabetes, hyperlipidemia. Importantly, disruption of fine tuning of the intracellular cortisol production - as it is regulated by 11β-HSD enzyme in specific adipose depots as well as in other essential metabolic organs also promotes metabolic syndrome phenotype.
Disrupted biological rythms such as those seen in sleep disorders and shift workers have been shown to increase the risk of metabolic disorders such as hyperglycemia, insulin resistance, central obesity and hypertension. Actually, loss of circadian rhythm and glucocorticoid excess conditions seem to develop similar metabolic disturbances; this indicate that the circadian CLOCK system and stress-responsive HPA axis strongly cooperate with each other in physiology and pathophysiology, however, details of such interaction at multiple levels remain largely unexplored.
Finally, epidemiological studies suggest a fetal programming of metabolic syndrome. It is now becoming increasingly accepted that intra-uterine and perinatal activation of HPA axis can cause epigenetic modifications which can lead to metabolic disturbances later in life.
Given that the prevalence of metabolic syndrome has reached epidemic levels, a better understanding of the role of HPA axis dysregulation in its pathophysiology and vice-versa will help us to better design prevention and treatment strategies.