The hypothalamic- pituitary -adrenal -leptin axis and metabolic health: A systems approach to resilience, robustness and control
van Wietmarschen, H.
Doyle III, F.J.
van der Greef, J.
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. © 2014 The Authors.
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