QUANTITATIVE ASSESSMENT OF THE FATES AND PHARMACOKINETICS OF CIRCULATING NUTRIENTS

Abstract

In mammals, the organs are fed by nutrients delivered via the bloodstream. These circulating nutrients can either come from internal stores within the body or from the diet, and can undergo interconversions with other nutrients before being burned as fuel. Additionally, circulating nutrients vary in the extent to which they are in rapid exchange with tissue metabolite pools as well as the rates at which they enter tissues. Thus, characterization of the fates and pharmacokinetics of circulating nutrients is essential to gaining a fundamental understanding of the metabolic demands of each tissue and the mechanisms by which those demands are met. Here, using isotope tracing, mass spectrometry, and mathematical modeling, we begin by quantifying the direct sources of the major circulating nutrients, their interconversion rates, and their tissue-specific contributions to TCA cycle metabolism in mice fed either a high carbohydrate diet or a high fat, very low carbohydrate ketogenic diet. We discover that circulating carbon flux is predominantly carried by two major metabolic cycles: the glucose-lactate and triglyceride-glycerol-fatty acid cycles. Futile cycling through these pathways is augmented when the dietary input of the corresponding nutrients is low, thereby rendering tissue metabolism robust to food availability. Next, we pivot our focus to study the pharmacokinetics of key circulating metabolites via similar methodology. We find that glucose possesses the smallest volume of distribution, equal to that of the extracellular fluid volume—a finding that is reported in the literature and supports the validity of our approach. Interestingly, we see that acetate, glycerol, glutamine, and lactate all exhibit volumes of distribution greater than the total body water volume indicating a mechanism for tissue trapping of these metabolites. Finally, we show inhibition of the lactate transporter MCT1 reduces lactate’s volume of distribution and circulatory turnover flux by 50%. In summary, the work described herein provides a novel quantitative framework within which the fates and pharmacokinetics of circulating nutrients can be probed across a wide variety of physiological, pathological, and pharmacological contexts.