title: Dynamical compensation in physiological circuits.
abstract: Biological systems can maintain constant steady-state output despite variation in biochemical parameters, a property known as exact adaptation. Exact adaptation is achieved using integral feedback, an engineering strategy that ensures that the output of a system robustly tracks its desired value. However, it is unclear how physiological circuits also keep their output dynamics precise-including the amplitude and response time to a changing input. Such robustness is crucial for endocrine and neuronal homeostatic circuits because they need to provide a precise dynamic response in the face of wide variation in the physiological parameters of their target tissues; how such circuits compensate their dynamics for unavoidable natural fluctuations in parameters is unknown. Here, we present a design principle that provides the desired robustness, which we call dynamical compensation (DC). We present a class of circuits that show DC by means of a nonlinear feedback loop in which the regulated variable controls the functional mass of the controlling endocrine or neuronal tissue. This mechanism applies to the control of blood glucose by insulin and explains several experimental observations on insulin resistance. We provide evidence that this mechanism may also explain compensation and organ size control in other physiological circuits.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Omer
authors.identifier: http://orcid.org/0000-0002-9426-5362
authors.initials: O
authors.lastname: Karin
authors.affiliation: Department of Developmental Biology and Cancer Research and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Swisa
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Department of Developmental Biology and Cancer Research and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel urialon@weizmann.ac.il.
authors.forename: Uri
authors.initials: U
authors.lastname: Alon
mesh_terms: D000222:Adaptation, Physiological; D025461:Feedback, Physiological; D008954:Models, Biological; D049490:Systems Biology / Q000379:methods*
keywords: calcium homeostasis; dynamical compensation; endocrine circuits; glucose homeostasis; mathematical models of disease