Flux organizations and control modes in antagonistically combined negative feedback loops

Area of Science:

• Systems biology
• Control theory
• Physiology

Background:

• Biological systems often employ multiple feedback mechanisms for stability.
• Understanding compensatory responses to environmental changes is crucial for physiology.
• Integral controllers are fundamental in maintaining homeostasis.

Purpose of the Study:

• To elucidate compensatory responses and control models when two antagonistic integral controllers are combined.
• To define and differentiate between delegated and isolated control mechanisms.
• To explore the phenomenon of rheostasis and its underlying control dynamics.

Main Methods:

• Analysis of combined integral controller systems.
• Modeling of compensatory flux regulations.
• Examination of environmental perturbations and their impact on control systems.

Main Results:

• Identification of two primary control types: delegated and isolated control, based on controller setpoints.
• Demonstration that interacting feedbacks can lead to rheostasis (environmentally driven setpoint changes).
• Proposal of metastable control and the impact of integral windup on setpoint stability.

Conclusions:

• The interaction of antagonistic integral controllers creates distinct regulatory models with implications for biological homeostasis.
• Rheostasis, exemplified by photoperiodic control in Siberian hamsters, can be explained by these interacting feedback systems.
• A dual-controller model offers insights into blood glucose homeostasis and the roles of key hormones.