Influences of methylprednisolone (MPL) and food consumption on body weight (BW), and the effects of MPL on glycemic control including food consumption and the dynamic interactions among glucose, insulin, and free fatty acids (FFA) were evaluated in normal male Wistar rats. Six groups of animals received either saline or MPL via subcutaneous infusions at the rate of 0.03, 0.1, 0.2, 0.3 and 0.4 mg/kg/h for different treatment periods. BW and food consumption were measured twice a week. Plasma concentrations of MPL and corticosterone (CST) were determined at animal sacrifice. Plasma glucose, insulin, and FFA were measured at various times after infusion. Plasma MPL concentrations were simulated by a two-compartment model and used as the driving force in the pharmacodynamic (PD) analysis. All data were modeled using ADAPT 5. The MPL treatments caused reduction of food consumption and body weights in all dosing groups. The steroid also caused changes in plasma glucose, insulin, and FFA concentrations. Hyperinsulinemia was achieved rapidly at the first sampling time of 6 h; significant elevations of FFA were observed in all drug treatment groups; whereas only modest increases in plasma glucose were observed in the low dosing groups (0.03 and 0.1 mg/kg/h). Body weight changes were modeled by dual actions of MPL: inhibition of food consumption and stimulation of weight loss, with food consumption accounting for the input of energy for body weight. Dynamic models of glucose and insulin feedback interactions were extended to capture the major metabolic effects of FFA: stimulation of insulin secretion and inhibition of insulin-stimulated glucose utilization. These models of body weight and glucose regulation adequately captured the experimental data and reflect significant physiological interactions among glucose, insulin, and FFA. These mechanism-based PD models provide further insights into the multi-factor control of this essential metabolic system.