Modeling energy intake by adding homeostatic feedback and drug intervention
Artikel i vetenskaplig tidskrift, 2015

Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction. The paper describes a model with the capability to capture physiological counter-regulatory feedback actions triggered by energy imbalances. This feedback is general as it handles tolerance to both increases and decreases in EI, and works in both acute and chronic settings. A drug mechanism function inhibits (or stimulates) EI. The deviation of EI relative to a reference level (set-point) serves as input to a non-linear appetite control signal which in turn impacts EI in parallel to the drug intervention. Three examples demonstrate the potential usefulness of the model in both acute and chronic dosing situations. The model shifts the predicted concentration-response relationship rightwardly at lower concentrations, in contrast to models that do not handle functional adaptation. A fourth example further shows that the model may qualitatively explain differences in rate and extent of adaptation in observed EI and its concomitants in both rodents and humans.

APPETITE

PERFECT ADAPTATION

Obesity

TOLERANCE

Pharmacology & Pharmacy

DYNAMICS

BODY-WEIGHT

Rebound

NONESTERIFIED FATTY-ACIDS

Appetite suppression

Weight

FOOD-INTAKE

Model-based drug discovery

Functional adaptation

INDUCED OBESE RATS

MATHEMATICAL-MODEL

BIOMARKERS

Författare

Peter Gennemark

Stephan Hjorth

Göteborgs universitet

J. Gabrielsson

Journal of Pharmacokinetics and Pharmacodynamics

1567-567X (ISSN) 1573-8744 (eISSN)

Vol. 42 79-96

Ämneskategorier

Farmakologi och toxikologi

DOI

10.1007/s10928-014-9399-4