In a 5-year project funded by the German Federal Ministry for Education and Research, we studied physiological networks related to hormonal regulation, energy and mineral metabolism of dairy cows in order to get a deeper understanding of the biological mechanism underlying the antagonistic relationship between milk yield and fertility in dairy cows.
For this purpose, we interactively developed predictive, dynamic models by fitting the models to experimental data and mechanistic knowledge. We have been working with two major models of physiological networks in dairy cow: a model for the bovine estrous cycle, named BovCycle, and a model for potassium balance. Both models are linked by a model for the glucose-insulin interaction that is known to influence both metabolic processes as well as hormonal regulation. For example, long term food reduction may lead to reversible functional disturbances in follicular development up to anestrus. There are common pharmaceutical interventions, as application of glucocorticoids, whose effects on potassium balance and reproduction have not yet been studied in detail.
In the bovine female, follicular maturation takes place in waves, and studies document a relationship between wave number, milk yield and fertility. The factors that regulate the number of waves are not fully explored, though experimental effort has been made to search for endocrine mechanisms that could be responsible for controlling these factors. Within the project, we studied the inter-individual variability in the number of follicular waves per estrous cycle based on the BovCycle model. We systematically identified those parameters and mechanisms that are responsible for changing the wave patterns. Prospectively, these findings provide candidate mechanisms for regulating wave patterns in the cow that might be explored experimentally. We also used an alternative model approach in terms of Boolean delay equations to study a switch in the oscillatory pattern upon changes in the model parameters and to simulate the administration of a hormone that is known to shift the estrous cycle in time.
The model of potassium balance in dairy cows is the basis for computer simulations of potassium intake, distribution in the organism, and excretion. The model has been developed and validated with experimental data from the Clinic for Ruminants at Freie Universität Berlin. In the potassium balance model we identified parameters for high and low potassium cows with an empirical approach, exploring the phenomenon that individuals show intracellular potassium concentrations of around either 20 mmol/l or 50 mmol/l. We demonstrated the extensibility and re-usability of this model by challenging it with a variety of experiments on potassium metabolism reflecting originating conditions of hypokalemia—reduced potassium intake, increased excretion, acid-base disturbances, and increased insulin.
The glucose-insulin model simulates the basic components on a level of organs and functional units. Simulation results qualitatively reproduce literature knowledge, particularly if environmental conditions are varied. We coupled the glucose-insulin model with the BovCycle models to explore the impact of glucose metabolism on the estrous cycle dynamics in dairy cows. Studying the system’s behavior gives new insights into short and long term effects and interactions, without the need for new animal experiments.