Elsevier

Diabetes & Metabolism

Volume 43, Issue 5, October 2017, Pages 401-410
Diabetes & Metabolism

Review
A synopsis of brown adipose tissue imaging modalities for clinical research

https://doi.org/10.1016/j.diabet.2017.03.008Get rights and content

Abstract

Body weight gain results from a chronic excess of energy intake over energy expenditure. Accentuating endogenous energy expenditure has been accorded considerable attention ever since the presence of brown adipose tissue (BAT) in adult humans was recognized, given that BAT is known to increase energy expenditure via thermogenesis. Besides classic BAT, significant strides in our understanding of inducible brown adipocytes have been made regarding its development and function. While it is ideal to study BAT histologically, its relatively inaccessible anatomical locations and the inherent risks associated with biopsy preclude invasive techniques to evaluate BAT on a routine basis. Thus, there has been a surge in interest to employ non-invasive methods to examine BAT. The gold standard of non-invasive detection of BAT activation is 18F-fluorodeoxyglucose positron emission tomography (PET) with computed tomography (CT). However, a major limitation of PET/CT as a tool for human BAT studies is the clinically significant doses of ionizing radiation. More recently, several other imaging methods, including single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), infrared thermography (IRT)/thermal imaging and contrast ultrasonography (US) have been developed in hopes that they would allow non-invasive, quantitative measures of BAT mass and activity with lower costs. This review focuses on such methods to detect human BAT activation and white adipose tissue (WAT) browning to prompt the establishment of BAT-centric strategies for augmenting energy expenditure and combatting obesity. Clinical validation of these methods will most likely expand the scope and flexibility of future BAT studies.

Introduction

Obesity is a worldwide epidemic associated with debilitating metabolic and cardiovascular sequelae, including diabetes, hypertension and dyslipidemia. The fundamental basis of the obesity crisis is a surplus of energy intake over energy expenditure. Excess calories are stored preferentially as triglycerides in white adipose tissue (WAT), a conserved evolutionary adaptation for maximum efficient energy reserves stored in fat tissue. Thus, WAT is an energy-storing tissue, whereas brown adipose tissue (BAT) dissipates energy in the form of heat. Indeed, the thermoregulatory function of BAT in small and hibernating mammals, including human neonates and infants, has been known for decades [1], [2]. Beyond the survival advantage conferred by this adaptation, overwhelming evidence that BAT activation can improve whole-body metabolism [3], [4], [5] has brought about a resurgence of research interest in BAT, especially since its presence was demonstrated in human adults by fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) with computed tomography (CT) in 2002 [6]. Recent evidence has also described the presence of brown adipocyte-like cells within WAT harbouring a similar phenotype to BAT called ‘beige’ or ‘brite’ (brown in white) adipocytes as distinct from ‘classic constitutive BAT’ [7]. As both classic brown and beige/brite adipocytes are thermogenic and expend stored energy, they add to the growing arsenal against obesity and diabetes [8]. There are many excellent reviews of BAT biology and its catabolic processes [9], [10], [11], whereas the present review focuses on the methodology for imaging BAT activation and WAT browning, with an emphasis on human applications, and highlights the advantages and drawbacks of each method.

Section snippets

BAT characteristics and WAT browning

In infants, classic brown adipocytes reside in depots anatomically localized to the interscapular, supraclavicular, pericardial, suprarenal and para-aortic regions. Beige/brite adipocytes in human adults can be found in fat tissue in the neck, supraclavicular areas, mediastinum (para-aortic), paravertebral and suprarenal regions. Supraclavicular and cervical BAT constitutes the two most abundant and readily inducible depots in most people [12]. At those sites, BAT is predominantly composed of

PET/CT imaging

Nowadays, PET/CT is an important cancer imaging tool for staging, restaging, treatment-monitoring and prognostication [43], surpassing either PET or CT alone and minimizing their individual limitations. Fluorodeoxyglucose (FDG) is a glucose analogue labelled with radioisotope fluorine-18 (18F). Like glucose, 18F-FDG can enter cells, mediated by structurally related glucose transport proteins (GLUTs), and then be phosphorylated by hexokinase as the first step towards glycolysis. Unlike glucose,

SPECT/CT imaging

Cold-stimulated BAT activation is mainly mediated by norepinephrine, released by the sympathetic nervous system (SNS), which can interact with β-adrenergic receptors to stimulate thermogenesis [12], [45]. SNS-induced BAT stimulation can be visualized using CT and single-photon emission computed tomography (SPECT), a three-dimensional functional nuclear medicine imaging technique using gamma rays produced by a gamma-emitting radioisotope. Emission intensity from the radioactive ligand is a

Magnetic resonance imaging

Human BAT can also be detected by MRI, as BAT has high intracellular and extracellular water contents, resulting in a higher water-to-fat ratio than WAT, an increased iron content, and high densities of mitochondria and blood vessels in BAT, thus resulting in lower T2 and T2* relaxation (Fig. 4) [76], [77]. As MRI produces no ionizing radiation (it uses non-ionizing radiofrequency pulses), it is more favourable and suitable for repeated BAT imaging in children and healthy populations. Fat

Infrared thermography imaging

A thermal imaging camera detects the infrared (IR) end of the electromagnetic spectrum and produces different images at different temperatures. As BAT is a thermogenic organ, it can transfer heat energy across the overlying skin through IR emission upon activation by a stimulus such as cold. Infrared thermography (IRT) has been used for BAT imaging in animals. In mouse studies, IRT images of histologically proven brown-fat depots have been reported to correlate well with 18F-FDG uptakes [88].

Near-infrared time-resolved spectroscopy

Near-infrared spectroscopy (NIRS) was initiated in 1977 by Jobsis [94] as a simple, non-invasive way to measure oxygen in muscle and other tissues in vivo. Near-infrared time-resolved spectroscopy (NIRTRS) is the method since developed to quantify optical properties such as absorption (μa) and scattering coefficients (μs), and total haemoglobin concentration (total Hb), the respective indices of tissue vasculature and mitochondrial content [95]. As BAT has an abundance of capillaries and

Ultrasound imaging

Contrast-enhanced ultrasonography (US) is a non-invasive way to estimate blood flow to a tissue by visualizing and quantifying intravenously infused microbubbles [99]. Contrast-enhanced US has long been used in cardiology, without ionizing radiation, and is validated for estimation of myocardial blood flow in humans [100]. Continuous real-time imaging using contrast-enhanced US has been shown to reliably detect microvascular blood volume changes in skeletal muscle and subcutaneous adipose

Conclusion

In addition to adipose tissue biopsy, a number of non-invasive imaging methods, including PET/CT, MRI, IRT, NIRTRS and contrast-enhanced US, can also be used to assess BAT. However, despite several recent imaging advances, each technique still has limitations and none is superior in all aspects for evaluating BAT comprehensively (Table 1). Tissue biopsy is still the only way to accurately distinguish classic from beige/brite BAT, as their Identified differences are currently at the cellular and

Disclosure of interest

The authors declare that they have no competing interest.

References (104)

  • F. Villarroya et al.

    Beyond the sympathetic tone: the new brown fat activators

    Cell Metab

    (2013)
  • J. Orava et al.

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

    Cell Metab

    (2011)
  • C. Quarta et al.

    11C-meta-hydroxyephedrine PET/CT imaging allows in vivo study of adaptive thermogenesis and white-to-brown fat conversion

    Mol Metab

    (2013)
  • K.Y. Chen et al.

    Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): recommendations for standardized FDG-PET/CT experiments in humans

    Cell Metab

    (2016)
  • M.A. Ochoa-Figueroa et al.

    Incidental uptake of 123I MIBG in brown fat

    Rev Esp Med Nucl Imagen Mol

    (2012)
  • B.F. Bernard et al.

    99mTc-MIBI, 99mTc-tetrofosmin and 99mTc-Q12 in vitro and in vivo

    Nucl Med Biol

    (1998)
  • J.D. Crane et al.

    A standardized infrared imaging technique that specifically detects UCP1-mediated thermogenesis in vivo

    Mol Metab

    (2014)
  • M.E. Symonds et al.

    Thermal imaging to assess age-related changes of skin temperature within the supraclavicular region co-locating with brown adipose tissue in healthy children

    J Pediatr

    (2012)
  • R. Vogel et al.

    The quantification of absolute myocardial perfusion in humans by contrast echocardiography: algorithm and validation

    J Am Coll Cardiol

    (2005)
  • R.E. Smith et al.

    Brown fat and thermogenesis

    Physiol Rev

    (1969)
  • M. Benito

    Contribution of brown fat to the neonatal thermogenesis

    Biol Neonate

    (1985)
  • A. Bartelt et al.

    The holy grail of metabolic disease: brown adipose tissue

    Curr Opin Lipidol

    (2012)
  • K.I. Stanford et al.

    Brown adipose tissue regulates glucose homeostasis and insulin sensitivity

    J Clin Invest

    (2013)
  • T.F. Hany et al.

    Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region

    Eur J Nucl Med Mol Imaging

    (2002)
  • J. Ishibashi et al.

    Medicine. Beige can be slimming

    Science

    (2010)
  • M. Giralt et al.

    White, brown, beige/brite: different adipose cells for different functions?

    Endocrinology

    (2013)
  • P. Lee et al.

    Brown adipose tissue in adult humans: a metabolic renaissance

    Endocr Rev

    (2013)
  • J. Wu et al.

    Adaptive thermogenesis in adipocytes: is beige the new brown?

    Genes Dev

    (2013)
  • J. Nedergaard et al.

    Unexpected evidence for active brown adipose tissue in adult humans

    Am J Physiol Endocrinol Metab

    (2007)
  • V. Ouellet et al.

    Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans

    J Clin Endocrinol Metab

    (2011)
  • M.C. Zingaretti et al.

    The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue

    FASEB J

    (2009)
  • P. Lee et al.

    High prevalence of brown adipose tissue in adult humans

    J Clin Endocrinol Metab

    (2011)
  • A. Bartelt et al.

    Brown adipose tissue activity controls triglyceride clearance

    Nat Med

    (2011)
  • S. Enerback

    The origins of brown adipose tissue

    N Engl J Med

    (2009)
  • S. Rousset et al.

    The biology of mitochondrial uncoupling proteins

    Diabetes

    (2004)
  • N.J. Rothwell et al.

    Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour

    Clin Sci (Lond)

    (1983)
  • S. Carobbio et al.

    Adipogenesis: new insights into brown adipose tissue differentiation

    J Mol Endocrinol

    (2013)
  • G. Barbatelli et al.

    The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation

    Am J Physiol Endocrinol Metab

    (2010)
  • K.A. Virtanen et al.

    Functional brown adipose tissue in healthy adults

    N Engl J Med

    (2009)
  • Y. Fukui et al.

    A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice

    Diabetes

    (2000)
  • M. Saito et al.

    High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity

    Diabetes

    (2009)
  • C. Cohade et al.

    “USA-Fat”: prevalence is related to ambient outdoor temperature-evaluation with 18F-FDG PET/CT

    J Nucl Med

    (2003)
  • C. Cohade et al.

    Uptake in supraclavicular area fat (“USA-Fat”): description on 18F-FDG PET/CT

    J Nucl Med

    (2003)
  • M. UD et al.

    Human brown adipose tissue [15O]O2 PET imaging in the presence and absence of cold stimulus

    Eur J Nucl Med Mol Imaging

    (2016)
  • M. Hadi et al.

    Brown fat imaging with 18F-6-fluorodopamine PET/CT, 18F-FDG PET/CT, and 123I-MIBG SPECT: a study of patients being evaluated for pheochromocytoma

    J Nucl Med

    (2007)
  • O. Muzik et al.

    Assessment of oxidative metabolism in brown fat using PET imaging

    Front Endocrinol (Lausanne)

    (2012)
  • K.Y. Chen et al.

    Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature

    J Clin Endocrinol Metab

    (2013)
  • T. Yoneshiro et al.

    Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men

    Obesity (Silver Spring)

    (2011)
  • S. Ben-Haim et al.

    18F-FDG PET and PET/CT in the evaluation of cancer treatment response

    J Nucl Med

    (2009)
  • M.E. Phelps et al.

    Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method

    Ann Neurol

    (1979)

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    These authors contributed equally to this article as co-first authors.

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