The hypothalamic–pituitary–adrenal–leptin axis and metabolic health: a systems approach to resilience, robustness and control

Abstract

Glucocorticoids contribute to obesity and metabolic syndrome; however, the mechanisms are unclear, and prognostic measures are unavailable. A systems level understanding of the hypothalamic–pituitary–adrenal (HPA)–leptin axis may reveal novel insights. Eighteen obese premenopausal women provided blood samples every 10 min over 24 h, which were assayed for cortisol, adrenocorticotropin releasing hormone (ACTH) and leptin. A published personalized HPA systems model was extended to incorporate leptin, yielding three parameters: (i) cortisol inhibitory feedback signalling, (ii) ACTH–adrenal signalling, and (iii) leptin–cortisol antagonism. We investigated associations between these parameters and metabolic risk profiles: fat and lean body mass (LBM; using dual-energy X-ray absorptiometry), and insulin resistance. Decreased cortisol inhibitory feedback signalling was significantly associated with greater fat (kg; p = 0.01) and insulin resistance ( p = 0.03) but not LBM. Leptin significantly antagonized cortisol dynamics in eight women, who exhibited significantly lower 24 h mean leptin levels, LBM and higher ACTH–adrenal signalling nocturnally (all p < 0.05), compared with women without antagonism. Traditional neuroendocrine measures did not predict metabolic health, whereas a dynamic systems approach revealed that lower central inhibitory cortisol feedback signalling was significantly associated with greater metabolic risk. While exploratory, leptin–cortisol antagonism may reflect a ‘neuroendocrine starvation’ response.