Metabolite Exchange between Mammalian Organs Quantified in Pigs

Abstract

SUMMARY Mammalian organs continually exchange metabolites via circulation, but systems-level analysis of this shuttling process is lacking. Here we compared, in fasted pigs, metabolite concentrations in arterial blood versus draining venous blood from 11 organs. Greater than 90% of metabolites showed arterial-venous differences across at least one organ. Surprisingly, the liver and kidneys released not only glucose but also amino acids, both of which were consumed primarily by the intestine and pancreas. The liver and kidneys exhibited additional unexpected activities: liver preferentially burned unsaturated over more atherogenic saturated fatty acids, while the kidneys were unique in burning circulating citrate and net oxidizing lactate to pyruvate, thereby contributing to circulating redox homeostasis. Furthermore, we observed more than 700 other cases of tissue-specific metabolite production or consumption, such as release of nucleotides by the spleen and TCA intermediates by pancreas. These data constitute a high-value resource, providing quantitative atlas of inter-organ metabolite exchange.

Identification of a Circulating Amino Acid Signature in Frail Older Persons with Type 2 Diabetes Mellitus: Results from the Metabofrail Study

“…Alanine and glutamic acid are crucial intermediates of muscle energy metabolism and liver-muscle metabolic interchange under both physiologic and pathologic conditions [51][52][53]. Perturbations in alanine and glutamate circulating pool may be indicative of skeletal muscle dysfunction, and are commonly encountered in age-related chronic conditions and models of muscle atrophy [54,55].…”

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

“…As the number of tissues increases, their roles could be more complicated rather than simple source and sink. For example, previous research indicates that the kidney may also have a significant contribution to net production of glucose in pigs (Jang et al, 2019). Second, more nutrient sources could be introduced and the metabolic network in each cell could also be expanded.…”

“…However, those studies have been limited by measurements that often included only a few metabolites. Recent studies have looked to quantitatively measure the utilization of nutrient sources at the systemic level using metabolic flux analysis (MFA) (Hui et al, 2017; Jang et al, 2019; Neinast et al, 2019). MFA is a methodology that seeks a solution of metabolic fluxes that best fits the isotope labeling data (i.e.…”

Quantitative fluxomics of circulating metabolites

“…In contrast to literature suggesting that the heart is an omnivore (Bing et al, 1954;Drake et al, 2012), cardiac muscle stands out for barely using amino acids as fuels, preferentially consuming fatty acids. Kidney is unique in burning circulating citrate (Jang et al, 2019). Pancreas shows the greatest use of amino acids.…”