Pharmacometric Characterization of Postprandial Responses and Taste Perception in Individuals with Obesity

Sammanfattning: Obesity is a major health epidemic worldwide and occurs when long-term excess of energy intake beyond energy utilization leads to an increase in adipose tissue. Energy balance is coordinated by the central nervous system regulation of appetite and adaptive thermogenesis via a complex array of neuropeptides which communicate to the periphery by various circulating measures dictating the utilization of various energy sources such as, carbohydrates, fat, or protein.  Given the complexity of interactions involved in energy balance, it is likely the cause of obesity is multifactorial.  This thesis sought to characterize obesity by developing models of postprandial response, pharmacologic intervention, and hedonic response and comparing the response between individuals who are lean to those who are obese or very obese.A semi-physiologic lipokinetic model was developed that described the postprandial triglyceride (TG) response of chylomicrons and very low-density lipoprotein (VLDL)-V6 in individuals who are lean, obese, and very obese. Postprandial TG differences in VLDL-V6 observed between individuals who are lean and those who are obese were attributed to individual insulin resistance, via HOMA-IR, on the transfer rate of chylomicrons to VLDL-V6.  Drug provocation within the model was investigated using a selective 5-hydroxytryptamine-2c receptor agonist, LY2140112.  The model found that increasing LY2140112 concentrations decreases the transfer rate of chylomicrons to VLDL-V6, counteracting the effect of insulin resistance in overweight and obese individuals. The lipokinetic model was integrated with the published integrated glucose-insulin model and glucagon-like peptide-1 model creating the TIGG model which incorporated key regulators of metabolism in a semi-mechanistic way.  The model elucidated important aspects of TG contribution to glucose homeostasis.Categorical models of the perception of sweetness, creaminess, and pleasantness were developed to compare among individuals who are lean to those who are obese or very obese and elucidated the complex relationship on the influence of the amount of fat and sugar on these scores.  A linked categorical model was developed using the individual predictions of creaminess and sweetness from the previously developed model as input into a categorical model for pleasantness response. The model using individual prediction of sweetness and creaminess showed an improvement to the model which used the amount of fat and sugar content in the solutions as covariates. The application of this approach provides an advancement within categorical modeling, showing how categorical models can be linked to enable the utilization of individual prediction.In conclusion, several models were developed to characterize obesity by comparing the response between individuals who are lean to those who are obese or very obese. These models can be useful in drug development for supporting obesity therapies.