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
]. 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 ice-cooled 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
] 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 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
]. An increased affinity 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 cold-stimulated 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 18F-FDG PET practice.