Model analysis of adipose tissue and whole body metabolism in vivo

Altered cellular metabolism can lead to metabolic disorders, such as insulin resistance, diabetes mellitus, and obesity. Quantitative analysis of cellular metabolic processes can provide insight into the regulatory mechanisms involved, which can lead to targets for the prevention and treatment of the metabolic abnormalities. Experimental studies of metabolic regulation in vivo accompanied by mechanistic mathematical modeling and simulation studies provide important insights into various physiological and pathophysiological states. In this study, metabolic regulation in adipose tissue and whole body was investigated by mathematical modeling and simulation related to in vivo experimental studies.;A multi-scale computational model of whole-body metabolism was developed to predict fuel homeostasis during exercise by incorporating hormonal regulation of cellular metabolic processes. The exercise induced changes in hormonal signals modulated metabolic flux rates of different tissues in a coordinated way in order to achieve glucose homeostasis. The model predicted the dynamic changes of hepatic glycogenolysis and gluconeogenesis. A higher contribution of glycogenolysis (∼75%) to glucose production during exercise was predicted. In addition, the model provided dynamic information on the relative contribution of carbohydrates and lipids to oxidative metabolism in skeletal muscle. Model simulations indicate that external fuel supplies from other tissue/organ systems to skeletal muscle become important for prolonged exercise emphasizing the significance of interaction among tissues.;A more detailed model of adipose tissue metabolism in vivo was developed to study regulation of triglyceride breakdown and synthesis. The model simulated and predicted physiological responses during intravenous epinephrine infusion and hyperinsulinemic-euglycemic clamp experiments. The model identified an active metabolic subdomain (∼3% of total tissue volume) in adipose tissue. Model simulations indicated that lipolytic reactions are differentially stimulated by epinephrine and differentially suppressed by insulin to produce distinctive changes in the lipolytic intermediates (i.e., diglycerides and monoglycerides). By incorporating two separate pools of triose phosphates in the adipose tissue, model simulations showed that glyceroneogenesis is the dominant pathway for glycerol-3-phosphate synthesis in response to epinephrine and insulin. Simulations also predict responses from altered enzyme activities. These models that predict alterations in metabolism can be used to determine critical experiments for specific therapeutic interventions.