Review Analysis of the Association between the Prevalence of Activated Brown Adipose Tissue and Outdoor Temperature

Brown adipose tissue (BAT) is important for regulating body weight. Environmental temperature influences BAT activation. Activated BAT is identifiable using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). 18F-FDG PET/CT scans done between June 2005 and May 2009 in our institution in tropical southern Taiwan and BAT studies from PubMed (2002–2011) were reviewed, and the average outdoor temperatures during the study periods were obtained. A simple linear regression was used to analyze the association between the prevalence of activated BAT (P) and the average outdoor temperature (T). The review analysis for 9 BAT studies (n = 16, 765) showed a significant negative correlation (r = −0.741, P = 0.022) between the prevalence of activated BAT and the average outdoor temperature. The equation of the regression line is P(%) = 6.99 − 0.20 × T  (°C). The prevalence of activated BAT decreased by 1% for each 5°C increase in average outdoor temperature. In a neutral ambient temperature, the prevalence of activated BAT is low and especially rare in the tropics. There is a significant linear negative correlation between the prevalence of activated BAT and the average outdoor temperature.


Introduction
Brown adipose tissue (BAT), with its thermogenic potential contributing to energy expenditure, is believed to influence body weight and age-related metabolic diseases [1,2]. It is potentially a candidate target tissue for anti-obesity therapies and has recently attracted much attention. BAT is abundant in newborns and helps protect them from lethal hypothermia [3]. In spite of the decrease in the amount of BAT with age, islets of brown adipocytes still endure in the white adipose tissue of adult humans [3,4]. The presence of this BAT, the recruitment of BAT, and the conversion of white into brown adipocytes may contribute to the development of new treatments for the current obesity pandemic [5,6].
Temperature-dependent BAT activation might be of interest in future approaches against obesity.
The primary thermoregulatory stimulus for activating BAT is a reduction in skin or external temperature [7]. BAT activation is more frequent during the cooler seasons of the year [8][9][10] and can be detected using 18 Ffluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET). Previous studies of the occurrence of activated BAT detected using 18 F-FDG PET are limited to the temperate zone, for example, North America and Europe. To further recognize its occurrence in tropical areas and to investigate the relationship between the prevalence of activated BAT and outdoor temperature over a wide range, we did a review analysis of data from our own patients and relevant studies from the PubMed database.  18 F-FDG and the dose was adjusted according to body weight in pediatric patients. Thereafter they stayed calmly in the supine position for 1 hour in an isolated, continuously air-conditioned room. An integrated PET/CT scanner (Discovery ST, GE Healthcare) was used to acquire images from the head to the upper part of the thighs. The images were reconstructed with an ordered-subset expectation maximization algorithm (OSEM, 2 iterations, 30 subsets). The transaxial PET data were obtained as 128 × 128-pixel images with a slice thickness of 3.27 mm. Coronal and sagittal sections, as well as maximum intensity projection PET images, were also reformatted for PET/CT imaging fusion and interpretation. 18 F-FDG PET/CT scans with reports stating that the patients had activated BAT were reviewed by 2 experienced nuclear medicine physicians to confirm the presence of activated BAT. Activated BAT was considered present if there were areas of increased 18 F-FDG uptake corresponding to the CT density of adipose tissue (−250 to −50 Hounsfield units) and compatible with characteristic patterns of BAT distribution ( Figure 1). This retrospective study was approved by our hospital's Institutional Review Board with a waiver of consent.

Literature Search.
We searched the PubMed database using the medical subject headings adipose tissue, brown, and (fluorodeoxyglucose F18 or positron-emission tomography) and retrieved English-language articles published from January 2002 through June 2011. We looked for studies that detected BAT using 18 F-FDG PET. Criteria for exclusion included nonhuman data; case reports; not a full paper; specialized subjects (such as pediatric patients, or only men or women); patients with a specific disease, with premedication or controlled temperature to influence BAT activation, repetitive data, and patients with BAT in a restricted anatomic distribution. Studies had to include definite information on the prevalence of activated BAT, where the study was done, and the months during which it was done.

Temperature Data and Statistical
Analysis. For our patients, we obtained the average outdoor temperature data from the Taiwan Central Weather Bureau. After we had identified the most relevant studies, we obtained the cities' average monthly temperatures during the respective study periods of interest from the official weather department websites of the countries in which the studies had been done. The average outdoor temperatures during the respective study periods were therefore acquired. We also grouped the 18 F-FDG PET/CT scans from our patients with activated BAT according to the season in which the PET/CT was done.
A simple linear regression was then done to analyze the association between the prevalence of activated BAT (P) and the average outdoor temperature (T) during the respective study periods. SPSS 17 for Windows (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. Significance was set at P < 0.05.

Results
In Seventy of these studies met at least 1 of the exclusion criteria and were rejected. Of the remaining 33 studies, 25 were considered ineligible after the full article was reviewed ( Figure 2). Eight studies fulfilled all of the inclusion criteria (Table 1)

Discussion
We found that the prevalence of 18 F-FDG PET-detected activated BAT was very low and varied considerably from 1.72% (for our patients living in a tropical climate) to 6.85% (for the other 8 cohorts in the reviewed literature) [8][9][10][11][12][13][14][15]. In the review analysis over a wide range of outdoor temperature, a simple linear regression analysis of all 9 cohorts showed a significant negative correlation between the prevalence of activated BAT and the average outdoor temperature during the study period. For each 5 • C increase in average outdoor temperature, the prevalence of 18 F-FDG PET-detected activated BAT decreased by 1%. This reinforces the importance of outdoor temperature for activating BAT and provides an estimation of the prevalence of activated BAT based on the outdoor temperature. In a thermoneutral environment, the formula from the result of this review analysis offers a baseline for reference and comparison. Previous studies have shown the influence of environmental temperature on the activation of BAT. By controlling the environmental temperature in a study with 56 healthy volunteers [16], the prevalence of activated BAT increased to 33% after the participants had been exposed to cold temperatures in the form of an intermittently applied icecooled footrest and a cool environmental temperature of 19 • C. In contrast, in a study on children [17], the prevalence of activated BAT decreased by two-thirds when the environmental temperature rose from 21 • C to 24 • C. In the current review, the two cohorts with the lowest prevalence of activated BAT were ours and the one in Yeung et al. [12]. The 18 F-FDG PET scans in the latter were done in New York City in July and August 2002, the hottest period in the temperate zone, when the temperature is similar to the high annual average temperature in tropical areas. We also found a seasonal variation in the prevalence of activated BAT that was consistent with other studies [8,9] and mainly due to the effect of the seasonal outdoor temperature. Further subgrouping the PET/CT scans from our patients with activated BAT according to the four seasons resulted in a more significant negative correlation and strengthened the regression relationship between activated BAT prevalence and outdoor temperature.
A recent study [18] with histological analysis found a high prevalence of BAT in adult humans, and the activated BAT detected by 18 F-FDG PET displayed strong immunoreactivity for uncoupling protein 1 (UCP1). UCP1 uncouples 4 The Scientific World Journal  adenosine-5 -triphosphate (ATP) synthesis from substrate oxidation in BAT to dissipate the electrochemical gradient as heat and is necessary for norepinephrine-induced glucose utilization [19]. Its activity depends on the availability of fatty acids delivered upon BAT's beta-adrenergic activation, which, physiologically, ensues from the sympathetic nervous system activation of the tissue [20]; exposure to cold is one of the most influential factors. Exposure to cold causes sympathetic stimulation of BAT, after which the cold stimulated BAT perfusion dependently dissipates energy, increases glucose utilization, and increases glucose transporter (GLUT) expression [21,22]. An increased affinity The Scientific World Journal 5 for or activation of the GLUT1 isoform is responsible for the norepinephrine-induced increase in glucose transport in brown adipocytes, and that is likely mediated by intracellular cAMP [23]. GLUT4 and UCP1 are more highly expressed in BAT than in white adipose tissue. Exposure to cold also increases the mRNA levels of GLUT4, an isoform of glucose transporters expressed in insulin-sensitive tissues in BAT [24]. These cellular components and molecular mechanisms may contribute to elevated 18 F-FDG accumulation in coldstimulated BAT.
The limitations of this study must be addressed. The review study is retrospective in nature. The average room temperatures (indoor) at which patients did their daily lives and received PET examinations as well as for how long they had been exposed to that particular temperature were not available for analysis. The average outdoor temperature during the study period we obtained cannot represent the actual temperature around every patient before their PET scan. However, we checked the actual daily temperature on every scan performed of our patients and the average was 25.3 • C, which was very close to the average monthly temperature of 25.4 • C during our study period. The difference is acceptable. Because of the diverseness of the published studies, we focused only on the outdoor temperature, the most important factor for BAT activation. Other factors that can influence BAT activation were not appropriately evaluated by this review analysis; however, our results provide an estimation of the occurrence of activated BAT for clinical 18 F-FDG PET practice.

Conclusion
In a neutral ambient temperature, the prevalence of activated BAT is low and especially rare in the tropical areas. In this review analysis, we found a significant negative correlation between the prevalence of activated BAT and the average outdoor temperature during the study period.