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

Aschbacher, Kirstin; Rodriguez-Fernandez, Maria; van Wietmarschen, Herman; Tomiyama, A. Janet; Jain, Shamini; Epel, Elissa; Doyle, Francis J., III; van der Greef, Jan


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.

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Título según WOS: ID WOS:000344472900005 Not found in local WOS DB
Título de la Revista: INTERFACE FOCUS
Volumen: 4
Número: 5
Editorial: ROYAL SOC
Fecha de publicación: 2014


Notas: ISI