The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents
Fig 5
Model-based in silico experimentation allows investigation of the effects of parameter changes, design of optimal dosing protocols, and testing of behavioural interventions.
(A) Schematic of refractory period experiment: following meal termination, access to food is prevented for a length of time (the refractory period). This is modelled by enforcing the intermeal interval to be at least the refractory period in length. (B) Introducing a refractory period into feeding behaviour reduces food intake to a similar degree as the administration of a high dose of PYY3-36 in simulated rats fed ad libitum in the dark period. (C) Food intake reduction occurs before the mean intermeal interval is substantially reduced, with a surprising dip in the intermeal interval when a short refractory period is introduced. (D) Schematic of optimal dosing experiment. All permutations of drug administrations, including at least 2 doses of saline, were tested with 10,000 in silico repeats. (E) Optimising drug administration schedules can reduce food intake by an additional 7% when feeding with zero initial fullness. Ad libitum-fed high-dose GLP-1, PYY3-36, and saline parameter values were used to simulate feeding behaviour with drug administration at different times. Error bars indicate standard error of the mean with 10,000 samples. Horizontal lines compare to refractory period reductions in food intake: dash-dotted and dashed lines indicate 15-minute and 30-minute refractory period food intakes for rats given saline, respectively. (F) The main effect of the optimal schedule is to reduce food intake once refed. Blue and red lines correspond to simulations using optimal administration protocol and control parameters, respectively. Shaded area indicates 95th percentile window of fullness. (G) Altering fullness decrease parameter k powerfully reduces food intake once refeeding is complete. A one-third reduction in k reduced 12-hour food intake by over 10 grams in simulated rats fed ad libitum given saline in the dark period. (H) Altering k over a plausible range linearly reduces food intake in simulated rats fed ad libitum given saline in the dark period. Dashed horizontal line indicates food intake typical of rats given high-dose PYY3-36. (I, J) Simplifying the model to predict meal termination with a sigmoid and intermeal interval with a linear regression (red lines) against fullness at meal termination shows good agreement with model-derived predictions (black lines). Details of simulation procedure in S1 Text. GLP-1, glucagon-like peptide 1; PYY3-36, peptide YY3-36.