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Insights into Brown Adipose Tissue Physiology as revealed by Imaging Studies a

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Chioma Izzi-Engbeaya , Victoria Salem , Rajveer S Atkar & Waljit S Dhillo

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Section of Investigative Medicine; Imperial College; London, UK Accepted author version posted online: 28 Oct 2014.Published online: 14 Nov 2014.

Click for updates To cite this article: Chioma Izzi-Engbeaya, Victoria Salem, Rajveer S Atkar & Waljit S Dhillo (2014): Insights into Brown Adipose Tissue Physiology as revealed by Imaging Studies, Adipocyte, DOI: 10.4161/21623945.2014.965609 To link to this article: http://dx.doi.org/10.4161/21623945.2014.965609

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REVIEW Adipocyte 4:1, 1--12; November 1, 2014; © 2014 Taylor & Francis Group, LLC

Insights into Brown Adipose Tissue Physiology as revealed by Imaging Studies Chioma Izzi-Engbeaya, Victoria Salem, Rajveer S Atkar, and Waljit S Dhillo* Section of Investigative Medicine; Imperial College; London, UK

Keywords: brown adipose tissue, energy expenditure, imaging, metabolism, thermogenesis

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Abbreviations: C-MHED, [11C]-meta-hydroxyephedrine; 18F-FDG, [18F]-fluorodeoxyglucose; 99mTc-sestamibi, technetium-99m sestamibi; 99mTc-tetrofosmin, technetium-99m tetrofosmin; ATP, adenosine triphosphate; BAT, brown adipose tissue; BMI, body mass index; BOLD, blood oxygen level dependent; CIT, cold-induced thermogenesis; IQR, interquartile range; MRI, magnetic resonance imaging; NST, non-shivering thermogenesis; PET-CT, positron emission tomography-computed tomography; SPECT, single photon emission CT; UCP-1, uncoupling protein 1; WAT, white adipose tissue.

There has been resurgence in interest in brown adipose tissue (BAT) following radiological and histological identification of metabolically active BAT in adult humans. Imaging enables BAT to be studied non-invasively and therefore imaging studies have contributed a significant amount to what is known about BAT function in humans. In this review the current knowledge (derived from imaging studies) about the prevalence, function, activity and regulation of BAT in humans (as well as relevant rodent studies), will be summarized.

Introduction Recent publications have unequivocally demonstrated the presence of thermogenically active brown adipose tissue (BAT) in adult humans and have led to renewed interest in the study of this type of adipose tissue. When activated, brown adipocytes release energy in the form of heat by uncoupling the protons generated by substrate oxidation from adenosine triphosphate (ATP) production. BAT cells express a special protein called UCP1 (uncoupling protein1/ thermogenin) which enables them to do this. Since activated BAT increases energy expenditure, it may play an important role in energy homeostasis and thus could be utilised in the treatment of obesity. Many techniques have been employed to study this unique tissue and imaging techniques in particular have enabled in vivo studies to be performed. This review will highlight the main imaging modalities that have been used to study BAT and summarise how each of these modalities has contributed to our knowledge of the characteristics and function of BAT in humans. Positron emission tomography - computed tomography (PET-CT) 18

F-FDG ([18F]-fluorodeoxyglucose)

PET-CT is the most widely used imaging modality currently used to study BAT. It consists of a functional scan in which *Correspondence to: Waljit S Dhillo; Email: [email protected] Submitted: 07/11/2014; Revised: 09/09/2014; Accepted: 09/11/2014 http://dx.doi.org/10.4161/21623945.2014.965609

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metabolically or biochemically active tissues are detected (i.e. the PET scan) and an anatomic scan (i.e., CT scan) performed at the same time. Following acquisition and processing of the images from both scans, they can be viewed individually or superimposed on each other to produce a single fused (or co-registered) image. [18F]-fluorodeoxyglucose (18F-FDG) is a tracer that is used to detect highly metabolically active tissue(s). 18F-FDG enters the metabolically active cells via specific glucose transporters and is then phosphorylated by hexokinase to its 6-phosphate. The 6-phosphate cannot be metabolised any further and therefore it is effectively trapped within the cell. The radioactive fluorine component of the tracer decays, and the products of its decay are detected by the PET scanner. The metabolically active tissues that have taken up the tracer can then be identified.1 PET-CT was initially used in clinical practice for identifying and staging malignant tumors. However, on these PET scans bilateral symmetric uptake was often noted in the neck and shoulder regions. Initially, this was thought to be due to active muscle, but CT scans of the same regions demonstrated that the tissues with this symmetrical uptake had the density of adipose tissue not muscle. These areas were called "USA-fat" (uptake of 18 F-FDG localizing to the supraclavicular area)1 and some authors felt that this represented BAT2,3 especially as the prevalence of “USA-fat” was found to be 3 times higher in winter (when outdoor temperatures were low) than the rest of the year.4 In 2009, Virtanen et al. demonstrated that the cold-induced increased 18F-FDG uptake seen on PET scans was due to paracervical and supraclavicular adipose tissue.5 These tissues were biopsied and found to have the cellular morphology of BAT and expressed UCP1 protein and mRNA.5 This study proved that not only is BAT present in adult humans, it is metabolically active and can be stimulated by cold.5 Two retrospective studies, which examined different series of over 3600 consecutive PETCT scans, found a prevalence of active BAT of »3% in men and 7.2–7.5% in women.6,7 A more recent and much larger retrospective study found a prevalence of active BAT of 1.32% in 31,088 PET-CT scans performed for medical check-ups (n D 16,699) and cancer surveillance (n D 14,389).8 Smaller cohort studies have reported a higher prevalence of cold-activated BAT

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(confirmed histologically) of 34% (19/56) in healthy volunteers aged 23–65 y in winter,9 48% (125/260) in healthy volunteers aged 20–72 y in winter,10 96% (23/24) of healthy men aged 20– 32 y with BMIs (body mass indexes) ranging from 21.3–38.8,11 and 20% (3/15) in morbidly obese volunteers.12 In these studies (which were performed in temperate regions) the prevalence and/or activity of detectable BAT was higher in winter/lower outdoor temperatures, younger subjects, females, in people with lower BMIs, lower blood glucose levels, lower percentages of body fat and lower quantities of visceral fat. In a study performed in a subtropical area, an inverse association between BAT 18F-FDG uptake and outdoor temperature was also observed.13 Furthermore the mass of BAT detected on 18F-FDG PET-CT scans decreases with increasing outdoor temperature, age and BMI, as well as being lower in men and in people with diabetes.14 Although lower BMIs are associated with a higher prevalence of active BAT, none of the 14 people with anorexia nervosa (BMI 15.3§0.8 in those with ongoing reduced calorie intake and BMI 18.8§1.1 in those who had been re-fed) imaged with 18F-FDG PET-CT in winter had increased uptake in BAT, but all of the 7 constitutionally lean people (BMI 16.2§0.9) had increased uptake in BAT.15 Therefore a low BMI does not necessarily predict the presence of active BAT, and chronic starvation in anorexia may reduce BAT activity. Some authors have investigated whether ethnicity influences BAT activity. A retrospective study of 386 scans did not reveal any differences in BAT uptake between Caucasians and Black Africans.13 Cold-stimulated BAT activity was found to be similar in Caucasians (n D 10) and South Asians (n D 10).16 In another study, although cold-induced BAT activity was similar between age- and BMI-matched male Caucasians (n D 11) and South Asians (n D 12), the volume of activated BAT was significantly lower in South Asians.17 Additionally, cold-induced/non-shivering thermogenesis increased in Caucasians by 20% but did not increase in South Asians exposed to the same conditions.17 Larger studies are required to determine whether ethnic differences in BAT activity exist, and whether there are any correlations between BAT activity/thermogenesis and metabolic phenotypes between different ethnicities. In children, the reported prevalence of active BAT in one retrospective review of 385 PET-CT scans performed on oncology patients aged 5-21 y was similar for boys (43.3%) and girls (45.3%), with peak activity seen in the 13–15 age group.18 Similarly to adults, BAT activity was inversely correlated with BMI, but in contrast to adults there was no correlation between BAT activity and outdoor temperature.18 However, in another study of scans performed during winter on people aged less than 21 years, 18F-FDG uptake was reduced from 31% to 5% by maintaining the room temperature where the subjects were placed at 24 C from 30 mins pre-tracer injection to 1-hour postinjection.19 The absence of increased 18F-FDG uptake may not necessarily mean that BAT is absent. In a prospective study of 17 people with preoperative PET-CT staging scans who had head and neck surgery, 3/17 (17.6%) had BAT detected by 18F-FDG with histological confirmation of BAT in regions corresponding to

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increased 18F-FDG uptake. However, histological analysis of the supraclavicular fat in the other 14 subjects who did not have increased 18F-FDG uptake on PET-CT revealed a mixture of adipocytes indistinguishable from white/subcutaneous fat and islands of adipocytes which contained multilobulated lipid droplets and expressed UCP1 (i.e. brown fat cells).20 It is feasible that in some subjects, islands of brown fat exist that are metabolically active but are below the spatial resolution threshold required for detection by the scanner. Therefore the prevalence of active BAT as detected by 18FFDG PET-CT ranges from 3 to 100% (Table 1) depending on the cohort studied, season, outdoor/indoor temperature and the nature of the study (retrospective review of scans vs. interventional study), and BAT may be present even though it is not detected by 18F-FDG PET-CT. Additionally, there may be a diurnal or meal-related variation in 18F-FDG uptake by BAT since in mice, 18F-FDG uptake by BAT was found to peak 9 hours into the light phase (i.e., when mice are less active) of a 12-hour light/12-hour dark day.31 The use of PET-CT has facilitated the identification and study of various stimulators and inhibitors of BAT activity, which are summarised in Figure 1. Cold exposure is the best known stimulator of BAT activity, and several 18F-FDG PETCT studies in humans using acute and/or chronic cold exposure are summarized in Table 1. The issue of whether cold-activated BAT actually results in significantly increased energy expenditure in humans has been addressed by several studies. In a randomized single-blind crossover study,25 24 participants (14 male and 10 female, mean age 28 years) spent 12 hours in a whole-room indirect calorimeter maintained at 24 C or 19 C after which a PETCT scan was performed. Thirty-six hours later the participants crossed over to the alternate study temperature followed by a second scan. During the study the participants received an individualized calorie-calculated caffeine-free diet consisting of 50% carbohydrate, 20% protein and 20% fat, wore hospital scrubs, slept with cotton sheets (and without blankets), and care was taken to ensure the participants did not shiver. This study demonstrated that cold-activated BAT results in a 5% increase in energy expenditure (with higher increases in energy expenditure in women and an inverse relationship between age and increased energy expenditure).25 Other studies have demonstrated a mean increase in energy expenditure of 3.1 kcal/day after cold exposure (15.5 C for 1 hour) in adults with a mean age of 29.6 years,26 and 250 kcal/day (after exposure to 19 C for 2 hours) in healthy young men with a mean age of 24.4 y22 Also in the latter study, chronic cold exposure (17 C for 2 hours a day for 6 weeks) in subjects with absent or low 18F-FDG uptake on baseline PET scanning resulted in increased 18F-FDG uptake and increased energy expenditure at week 6.22 In a different study, chronic cold exposure (10 C for 2 hours per day for 4 weeks) increased BAT volume by 45%, as well increased BAT oxidative metabolism and fractional glucose uptake.30 These studies have demonstrated that BAT in adult humans can be activated (and recruited) resulting in significant increases in energy expenditure and metabolic activity, which can potentially be exploited to develop agents to treat obesity.

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Subjects kept in room temperature of 19 C for 2 hours prior to scan. During scan one foot placed intermittently (for 4 mins every 5 mins) on icecooled footrest.

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Insights into Brown Adipose Tissue Physiology as Revealed by Imaging Studies.

There has been resurgence in interest in brown adipose tissue (BAT) following radiological and histological identification of metabolically active BAT...
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