Determination of a pharmacokinetic model for [11C]-acetate in brown adipose tissue

Abstract

Background [ 11 C]-acetate positron emission tomography is used to assess oxidative metabolism in various tissues including the heart, tumor, and brown adipose tissue. For brown adipose tissue, a monoexponential decay model is commonly employed. However, no systematic assessment of kinetic models has been performed to validate this model or others. The monoexponential decay model and various compartmental models were applied to data obtained before and during brown adipose tissue activation by cold exposure in healthy men. Quality of fit was assessed visually and by analysis of residuals, including the Akaike information criterion. Stability and accuracy of compartmental models were further assessed through simulations, along with sensitivity and identifiability of kinetic parameters. Results Differences were noted in the arterial input function between the warm and cold conditions. These differences are not taken into account by the monoexponential decay model. They are accounted for by compartmental models, but most models proved too complex to be stable. Two and three-tissue models with no more than four distinct kinetic parameters, including blood volume fraction, provided the best compromise between fit quality and stability/accuracy. Conclusion For healthy men, a three-tissue model with four kinetic parameters, similar to a heart [ 11 C]-palmitate model seems the most appropriate based on model stability and its ability to describe the main [ 11 C]-acetate pathways in BAT cells. Further studies are required to validate this model in women and people with metabolic disorders. Electronic supplementary material The online version of this article (10.1186/s13550-019-0497-6) contains supplementary material, which is available to authorized users.

14-3-3ζ mediates an alternative, non-thermogenic mechanism in male mice to reduce heat loss and improve cold tolerance

“…The tissue (except BAT) blood flow index [K 1 in min −1 of [ 11 C]-acetate and oxidative metabolism index (K 2 in min −1 of [ 11 C]-acetate) were estimated from [ 11 C]-acetate by using a three-compartment model [ 41 ]. BAT K 1 and K 2 were estimated from [ 11 C]-acetate by using a new multicompartment model specific to BAT [ 42 ]. Tissue glucose fractional extraction (Ki – i.e.…”

Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

“…Although cold stress increases lipolysis in the BAT and WAT, it also increases de novo lipogenesis and fatty acid re-esterification. Cold stress increases uptake of acetates into the BAT, which then is converted to acetyl-CoA to undergo either direct oxidation via the citric acid cycle or fatty acid synthesis [66]. In this regard, lipogenesis is an important anabolic process employed by the BAT to produce free fatty acids that can be used subsequently as a fuel for β-oxidation.…”

Contribution of perfusion to the 11C‐acetate signal in brown adipose tissue assessed by DCE‐MRI and 68Ga‐DOTA PET in a rat model

“…The similar rates of oxidation and 11 C-CO 2 elimination in the 11 C-acetate model is an arbitrary constraint imposed to stabilize the model. 10 Data with better SNR and time resolution may allow more complex models. Other AIF extraction methods, such as principal component analysis, 68 could also be considered, but they would need validation against blood sampling.…”

“…34,58,59 So far, we relied on the monoexponential decay model (K mono ) for quantification and found that fit quality was poor in certain circumstances, especially at thermoneutrality. 10 The four-compartment model was suggested as a more reliable alternative which could also quantify uptake and storage of metabolites. However, there were some issues with coupling of parameters (K 1 and k 2 ) as well as the impact of the blood signal (v b ).…”

“…In a previous article, we proposed a four-compartment pharmacokinetic model to distinguish oxidation and lipid synthesis. 10 However, BAT can undergo large perfusion changes along with activation by cold or sympathomimetics, [11][12][13][14] although metabolism and perfusion are sometimes uncoupled. 13,15 Perfusion affects the 11 C-acetate signal and must be considered for precise assessment of oxidation.…”