Regulation of human brown adipose tissue by adenosine and A 2A  receptors – studies with [ 15 O]H 2 O and [ 11 C]TMSX PET/CT

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Abstract

Purpose

Brown adipose tissue (BAT) has emerged as a potential target to combat obesity and diabetes, but novel strategies to activate BAT are needed. Adenosine and A _2A receptor (A2AR) agonism activate BAT in rodents, and endogenous adenosine is released locally in BAT as a by-product of noradrenaline, but physiological data from humans is lacking. The purpose of this pilot study was to investigate the effects of exogenous adenosine on human BAT perfusion, and to determine the density of A2ARs in human BAT in vivo for the first time, using PET/CT imaging.

Methods

Healthy, lean men ( n = 10) participated in PET/CT imaging with two radioligands. Perfusion of BAT, white adipose tissue (WAT) and muscle was quantified with [ ¹⁵O]H ₂O at baseline, during cold exposure and during intravenous administration of adenosine. A2AR density of the tissues was quantified with [ ¹¹C]TMSX at baseline and during cold exposure.

Results

Adenosine increased the perfusion of BAT even more than cold exposure (baseline 8.3 ± 4.5, cold 19.6 ± 9.3, adenosine 28.6 ± 7.9 ml/100 g/min, p < 0.01). Distribution volume of [ ¹¹C]TMSX in BAT was significantly lower during cold exposure compared to baseline. In cold, low [ ¹¹C]TMSX binding coincided with high concentrations of noradrenaline.

Conclusions

Adenosine administration caused a maximal perfusion effect in human supraclavicular BAT, indicating increased oxidative metabolism. Cold exposure increased noradrenaline concentrations and decreased the density of A2AR available for radioligand binding in BAT, suggesting augmented release of endogenous adenosine. Our results show that adenosine and A2AR are relevant for activation of human BAT, and A2AR provides a future target for enhancing BAT metabolism.

Electronic supplementary material

The online version of this article (10.1007/s00259-018-4120-2) contains supplementary material, which is available to authorized users.

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Most cited references 27

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Adenosine receptors as drug targets--what are the challenges?

Bertil Fredholm, Jiang-Fan Chen, Holger Eltzschig (2013)

Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors--either directly or indirectly--have now entered the clinic. However, only one adenosine receptor-specific agent--the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma)--has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.

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Different metabolic responses of human brown adipose tissue to activation by cold and insulin.

Janne Orava, Pirjo Nuutila, Martin E. Lidell … (2011)

We investigated the metabolism of human brown adipose tissue (BAT) in healthy subjects by determining its cold-induced and insulin-stimulated glucose uptake and blood flow (perfusion) using positron emission tomography (PET) combined with computed tomography (CT). Second, we assessed gene expression in human BAT and white adipose tissue (WAT). Glucose uptake was induced 12-fold in BAT by cold, accompanied by doubling of perfusion. We found a positive association between whole-body energy expenditure and BAT perfusion. Insulin enhanced glucose uptake 5-fold in BAT independently of its perfusion, while the effect on WAT was weaker. The gene expression level of insulin-sensitive glucose transporter GLUT4 was also higher in BAT as compared to WAT. In conclusion, BAT appears to be differently activated by insulin and cold; in response to insulin, BAT displays high glucose uptake without increased perfusion, but when activated by cold, it dissipates energy in a perfusion-dependent manner. Copyright © 2011 Elsevier Inc. All rights reserved.

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Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects.

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A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t after which a plot of integral of t0ROI(t')dt'/ROI(t) versus integral of t0Cp(t')dt'/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume,.Vp. For a two-compartment model, the slope is given by lambda + Vp, where lambda is the partition coefficient and the intercept is -1/[kappa 2(1 + Vp/lambda)]. For a three-compartment model, the slope is lambda(1 + Bmax/Kd) + Vp and the intercept is -[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 +/- 0.20, in agreement with literature values.

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Author and article information

Contributors

Kirsi A. Virtanen: +358407626564 , kirsi.virtanen@utu.fi

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur. J. Nucl. Med. Mol. Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 13 August 2018

Publication date PMC-release: 13 August 2018

Publication date (Print): 2019

Volume: 46

Issue: 3

Pages: 743-750

Affiliations

[1 ]ISNI 0000 0001 2097 1371, GRID grid.1374.1, Turku PET Centre, , University of Turku, ; P.O. Box 52, FI-20520 Turku, Finland

[2 ]ISNI 0000 0004 0628 215X, GRID grid.410552.7, Turku PET Centre, , Turku University Hospital, ; Turku, Finland

[3 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Institute of Pharmacology and Toxicology, , University of Bonn, ; Bonn, Germany

[4 ]ISNI 0000 0004 0628 215X, GRID grid.410552.7, Department of Endocrinology, , Turku University Hospital, ; Turku, Finland

Article

Publisher ID: 4120

DOI: 10.1007/s00259-018-4120-2

PMC ID: 6351510

PubMed ID: 30105585

SO-VID: 016d508a-4dc4-4b24-b79c-e812561edd95

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 7 January 2018

Date accepted : 1 August 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002341, Academy of Finland;

Award ID: 259926, 265204, 292839, 269977

Award Recipient : Kirsi A. Virtanen

Funded by: FundRef http://dx.doi.org/10.13039/501100007417, Paulon Säätiö;

Funded by: FundRef http://dx.doi.org/10.13039/501100008413, Instrumentariumin Tiedesäätiö;

Funded by: Turku University Hospital Research Funds

Funded by: FundRef http://dx.doi.org/10.13039/501100005609, Turun Yliopisto;

Custom metadata

ScienceOpen disciplines: Radiology & Imaging

Keywords: brown adipose tissue,adenosine,a2a receptor,perfusion,physiology,positron emission tomography,[11c]tmsx,[15o]h2o

Data availability:

ScienceOpen disciplines: Radiology & Imaging

Keywords: brown adipose tissue, adenosine, a2a receptor, perfusion, physiology, positron emission tomography, [11c]tmsx, [15o]h2o