The “principle of balance“: How do biological systems become homeostatic?

Most biological systems are feedback regulated and aim to a homeostasis after a deflection. A feedback regulation by two different receptors assures highest flexibility and stability for a system and permits biphasic dose response curves, which are very common in neuroendocrinology. Based on this knowledge we formulated a general principle of homeostasis. We hypothesized that this principle is applicable to the feedback regulation of the hypothalamus pituitary adrenal (HPA) system by the Mineralocorticoid and the Glucocorticoid Receptor (MR and GR) in the brain. We developed a system of differential equations describing the HPA-System. In these differential equations MR was defined as stimulatory and GR as inhibitory. Clinical data (including concentrations of cortisol, ACTH, and cortisol binding globulin (CBG)) were derived from various experiments examining the HPA-System. These data were individually analyzed using the differential equations. A parameter identification was performed to determine the efficacy for brain MR, brain GR, CRH, ACTH, and peripheral GR for each subject. For validation, the identified parameters were used for reconstruction of ACTH and cortisol curves that were compared with the clinical data curves. This procedure enabled us to discriminate between subjects identifying their individual parameters that regulate HPA-System activity. For example, we found that subjects with obesity have higher efficacy of central MR and lower efficacy of central GR than subjects with normal body mass (ANOVA; P<0.01). The reconstructed ACTH and cortisol curves fit well to the clinical data curves (prediction error 0.02–0.17). In fact, our new system of differential equations based on the principle of homeostasis predicted the HPA-System activity with a wider area of validity than previously used models, which were based on a tonic inhibitory feedback (identification error 0.17 vs. 0.68, in ADX/Cushing disease). For the first time, our system of differential equations permits the identification of brain parameters regulating the HPA system activity that are normally not reachable in vivo.