A novel clinical approach to evaluating changes in fat oxidation in healthy, overnight-fasted subjects

Abstract

Obesity is characterized by impaired fat oxidation, and, therefore, the development of therapeutics designed to enhance fat oxidation for treating obesity is a growing focus in drug discovery. Evaluating such agents, however, is challenging in a clinical setting; requisite overnight fasting prior to a study visit increases whole body fat oxidation in lean, healthy subjects, making incremental increases potentially difficult to detect. We recruited 16 lean/overweight participants and eight obese participants to evaluate novel methodology designed to optimally detect increases in fat oxidation. Carbohydrate intake was increased for three days leading up to the overnight test visit and evaluated as either a standalone strategy to suppress overnight fasting-related increases in fat oxidation or was combined with overnight administration of IV glucose in a subset of lean/overweight subjects. Indirect calorimetry was performed the following morning to examine the degree to which these interventions were able to diminish fasting related increases in fat oxidation. Fat oxidation was then subsequently stimulated by challenging patients with a lipid infusion to determine the importance of the preceding interventions on the ability to detect statistically significant increases in fat oxidation. In lean/overweight subjects, suppression of fasting-related increases in fat oxidation via increased dietary carbohydrate intake was not necessary to detect subsequent meaningful increases in fat oxidation rates following Intralipid infusion; however, a statistically significant decrease in respiratory quotient following Intralipid infusion could only be observed when the infusion was preceded with high carbohydrate dietary intake. Glucose infusion, which further suppressed fasting-related fat oxidation, in turn led to more dramatic increases in Intralipid-driven fat oxidation. Both lean/overweight and obese subjects could demonstrate statistically significant increases in fat oxidation following Intralipid infusion, a finding which supports the inclusion of obese subjects in similar future clinical studies. Lastly, serum levels of β-hydroxybutyrate correlated strongly with fat oxidation rates, as well as respiratory quotient, suggesting potential as a surrogate biomarker of fax oxidation. Taken together, we demonstrate the utility of novel methodology to facilitate measuring changes in fat oxidation in lean/overweight and obese human volunteers in a clinical setting similar to that needed to test drugs designed to increase fat oxidation.