A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

Abstract

Regulation of lipolysis in adipose tissue is critical to whole body fuel homeostasis and to the development of insulin resistance. Due to the challenging nature of laboratory investigations of regulatory mechanisms in adipose tissue, mathematical models could provide a valuable adjunct to such experimental work. We have developed a computational model to analyze key components of adipose tissue metabolism in vivo in human in the fasting state. The various key components included triglyceride-fatty acid cycling, regulation of lipolytic reactions, and glyceroneogenesis. The model, consisting of spatially lumped blood and cellular compartments, included essential transport processes and biochemical reactions. Concentration dynamics for major substrates were described by mass balance equations. Model equations were solved numerically to simulate dynamic responses to intravenous epinephrine infusion. Model simulations were compared with the corresponding experimental measurements of the arteriovenous difference across the abdominal subcutaneous fat bed in humans. The model can simulate physiological responses arising from the different expression levels of lipases. Key findings of this study are as follows: (1) Distinguishing the active metabolic subdomain (~3% of total tissue volume) is critical for simulating data. (2) During epinephrine infusion, lipases are differentially activated such that diglyceride breakdown is ~4 times faster than triglyceride breakdown. (3) Glyceroneogenesis contributes more to glycerol-3-phosphate synthesis during epinephrine infusion when pyruvate oxidation is inhibited by a high acetyl-CoA/free-CoA ratio.

The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

“…Furthermore, we cannot exclude a potential increase in pyruvate dehydrogenase (PDH) activity in ROR sg/sg mice that could increase the decarboxylation of pyruvate to acetyl-CoA and thus decrease the C 1 -pyruvate availability for glyceroneogenesis. Nevertheless, high levels of acetyl-CoA resulted in the inhibition of pyruvate decarboxylation by suppressing PDH, making more pyruvate available for glyceroneogenesis (21). Furthermore, our demonstration of a common decrease in PEPCKc at the level of mRNA, protein, and specific activity in ROR sg/sg mice consolidates our functional data based on pyruvate incorporation into TG.…”

Mathematical modelling of hepatic lipid metabolism

“…in skeletal muscle [36,12], in adipose tissue [33,31] and in the brain [45]. These models tend to rely on flux balance analysis to obtain information about large scale metabolic networks at steady state, and are thus not always suitable for studying postprandial dynamics.…”

Evaluating computational models of cholesterol metabolism

“…By modeling triglycerides in liver separated over four different compartments, it is implicitly assumed that such a distinction bears physiological relevance. At least in adipose tissue this has been suggested to be the case [80,81]. The authors predict that LXR-agonist treatment induces a reduction in VLDL-particle secretion and a reduction of the HDL cholesterol uptake capacity.…”