Fig 1.
Work-flow for comparison of existing model terms and construction of refined model.
Jelic, Pratt, and Sips model terms are compared for each metabolite flux separately using the postprandial arteriovenous tracer measurements from the Yoyo study. Existing model terms are first evaluated based on their ability to describe the experimentally measured data. In addition, as the refined model is constructed with the aim that parameters could be estimated directly from measured data, existing model terms are also compared using identifiability analysis, using the Profile Likelihood, sensitivity analysis, and statistical evaluation using Akaike Information Criterion. The refined model of adipose tissue metabolism is constructed either by selecting the best fitting of the existing model terms, or by introducing modifications and, where necessary, novel physiological mechanisms. The resulting refined model is then parameterised using data from both the baseline and following weight stabilisation from the Yoyo study, and the values compared.
Fig 2.
Structure of refined mathematical model of adipose tissue metabolism.
The refined model of adipose tissue metabolism consists of a two compartmental model, describing dynamics between the plasma and a lumped interstitial adipose space. The insulin stimulated LPL lipolysis of circulating triglycerides releases glycerol and NEFA. The hydrolysed NEFA passes into the adipose space, with an insulin-dependent fraction spilling over into the plasma. The insulin inhibited lipolysis of the triglycerides stored within the adipose tissue releases NEFA and glycerol. It is assumed that this glycerol cannot be recycled within the adipose space and enters the plasma for transportation to the liver. Glucose passes into the adipose space at an insulin dependent and independent rate. Glucose is converted to G-3-P and provides the glycerol backbone necessary for re-esterification of NEFA for storage as triglyceride within the adipose space. Novel model terms, introduced in this analysis, are shown in red, existing models are shown in black. Reactions that are stimulated by insulin are depicted with a green insulin symbol. Reactions that are inhibited by insulin are shown with a red insulin symbol.
Fig 3.
Comparison of the Jelic, Pratt, Sips, and refined model fit to baseline flux data from the Yoyo study.
The fit of the refined model to the baseline adipose tissue flux data from the Yoyo Study is shown along with the terms from the Jelic, Pratt, and Sips models simulated using the parameter values provided in the respective publications. (A) Model terms from the Pratt (green), Jelic (blue), Sips (yellow), and refined model (red) describing the postprandial LPL mediated lipolysis of circulating triglycerides are shown. (B) Terms describing the fractional spill over of LPL derived NEFA from the Pratt, Sips, and refined adipose tissuse models are shown. The mean fractional spill over values, calculated using the postprandial palimate [U-13C] tracer included in the meal (black crosses ± standard error of mean). (C) Model terms describing the uptake of glucose into the adipose tissue from the Pratt and refined model are shown. (D) Depicts terms describing the postprandial efflux of glucose from the Pratt and refined models. (E) Model terms describing the efflux NEFA from the abdominal subcutaneous adipose tissue from the Pratt, Sips, Jelic, and refined models are shown. Metabolite fluxes are calculated as the arteriovenous difference in a metabolite across the adipose tissue multiplied by the rate of postprandial adipose tissue blood flow. The mean calculated adipose tissue fluxes are shown with the black crosses ± the standard error of the mean. Negative flux values indicate a net release of the metabolite from the adipose space, positive values indicate a net uptake.
Fig 4.
Fitting of the refined model to adipose tissue flux data measured at baseline and following caloric restriction from the Yoyo study.
The refined model was fit to postprandial adipose tissue flux measurements of (A) LPL mediated lipolysis of circulating triglycerides, (B) the fractional spill over of LPL derived NEFA, (C) infflux of glucose, and efflux of both (D) glycerol, and (E) NEFA to the adipose tissue at baseline and following a period of caloric restriction. Blue crosses indicate the mean adipose tissue flux at baseline, the red crosses show the mean flux following caloric restriction, error bars indicate the standard error of the respective means. Refined model prediction at baseline is shown in blue, and the model fit following the diet intervention is shown in red. Negative flux values indicate a net release of the metabolite from the adipose space, positive values indicate a net uptake.
Fig 5.
Postprandial uptake of glycerol by adipose space.
A) Mean postprandial triglyceride influx (blue) (equivalent to the release of glycerol by LPL lipolysis (red)) and total glycerol efflux (yellow) across the abdominal subcutaneous adipose tissue at baseline in the Yoyo study (± standard error of the mean). B) Mean (± standard error of the mean) of glycerol flux minus triglyceride flux in postprandial phase measured at baseline in the Yoyo study indicating a net uptake of glycerol by the abdominal subcutaneous adipose tissue in the postprandial condition (green shaded region). This is in contradiction to the commonly held assumption that the glycerol efflux equals the direct sum of glycerol released by LPL lipolysis of circulating triglyceride and glycerol released by ATL lipolysis within the adipose tissue.
Table 1.
Parameter values estimated for data collected at baseline and following caloric restriction.
Fig 6.
Decomposition of model glycerol and NEFA flux predictions into constituent reactions.
Comparison of model predictions of rates of reactions contributing to the (A) glycerol flux in the plasma compartment, (B) rates of glycerol rate of reactions in adipose compartment, (C) plasma and adipose compartment glycerol concentrations, (D) NEFA flux in the plasma compartment, (E) rates of NEFA reaction in adipose compartment, and (F) plasma and adipose compartment NEFA concentrations. Solid lines represent baseline estimates and dashed lines represents estimates following weight stabilisation.