title: 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.
authors.affiliation: Department of Psychiatry , University of California , San Francisco, CA , USA ; The Institute for Integrative Health , Baltimore, MD , USA.
authors.forename: Kirstin
authors.identifier: 0000-0001-6191-6432
authors.initials: K
authors.lastname: Aschbacher
authors.affiliation: Department of Chemical Engineering , University of California , Santa Barbara, CA , USA.
authors.forename: Maria
authors.identifier: 0000-0002-8598-5229
authors.initials: M
authors.lastname: Rodriguez-Fernandez
authors.affiliation: TNO Innovation for Life , Zeist , The Netherlands ; Department of Analytical Biosciences , Leiden University , Leiden , The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: van Wietmarschen
authors.affiliation: Department of Psychology , University of California , Los Angeles, CA , USA.
authors.forename: A Janet
authors.identifier: 0000-0002-2152-5813
authors.initials: AJ
authors.lastname: Tomiyama
authors.affiliation: Department of Brain, Mind & Healing , Samueli Institute , Alexandria, VA , USA ; Department of Psychiatry , University of California , San Diego, CA , USA.
authors.forename: Shamini
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Psychiatry , University of California , San Francisco, CA , USA.
authors.forename: Elissa
authors.identifier: 0000-0002-9334-4720
authors.initials: E
authors.lastname: Epel
authors.affiliation: Department of Chemical Engineering , University of California , Santa Barbara, CA , USA.
authors.forename: Francis J
authors.identifier: 0000-0001-5342-4083
authors.initials: FJ
authors.lastname: Doyle
authors.affiliation: TNO Innovation for Life , Zeist , The Netherlands ; Department of Analytical Biosciences , Leiden University , Leiden , The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: van der Greef
keywords: dynamic systems; metabolic syndrome; obesity; psychological stress; robustness; stress-eating