To explore the relationship between BAT activity and neoplastic status, we used 18F-FDG PET/CT to determine the distribution and TMA of activated BAT in our patients living in the tropics, where the influence of outdoor temperature was low and the effect of neoplastic status on the activation of BAT could be more clearly determined. We found that neoplastic status was a critical determinant of BAT activity.
In limited numbers of patients, a high prevalence of activated BAT has been reported in patients with lymphoma (17%) and in female patients with breast cancer (80%) [16
]. Light-microscopic examination of necropsy specimens of periadrenal tissue has shown that the prevalence of BAT is higher in patients with cancer cachexia (80%) than in age-matched controls [3
]. Moreover, animal studies have shown that cancer cachexia due to an increased metabolic rate may be mediated by sympathetic stimulation and subsequent BAT thermogenesis with overexpression of UCP1 [18
]. Cancer patients have very high chronic stress responses caused by psychosocial distress [20
]. The biological consequences of cumulative stress include catecholamine hyperactivity of the sympathetic nervous system (SNS) response [22
], and the SNS plays a key role in the activation of BAT. Our study, which reduced the interference of low outdoor temperature, further demonstrates that more active neoplastic status was associated with more vigorous TMA of BAT.
Our patients with neoplastic status scores of 2 were thought to have either malignancies, inflammatory lesions, or a combination of the two. We hypothesize that inflammation also strongly influences the metabolic activity of BAT in our patients with activated BAT. Inflammatory stimulated pain and stress can activate the fight-or-flight response with subsequent increases in adrenaline and noradrenaline. Lechin et al. [23
] reported significant increases in plasma catecholamines in various patient groups during periods of disease exacerbation. The hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system are both activated during inflammation as an elaborate multi-directional communication pathway designed to restore homeostasis, in part by regulating the inflammatory and subsequent immune responses. Efferent signals are relayed to the site(s) of inflammation primarily by the secretion of norepinephrine from efferent sympathetic neurons and of epinephrine from the adrenal medulla [24
]. On the other hand, tumor necrosis factor alpha (TNF-α, cachectin), a potential mediator of cancer cachexia and the dysregulation of inflammation, increases the thermogenic activity of BAT and the rate of fatty acid synthesis from glucose in BAT assayed in vitro
]. These processes provide a reasonable explanation for the association between neoplastic status/inflammation and BAT metabolic activity.
Several factors may affect the activation of BAT. The conversion of white to brown adipocytes can be induced by β-adrenergic stimulation with hormones (catecholamines) that are released in response to stress or low blood sugar [27
]. Activated BAT is not present in relevant quantities in adults except during sympathetic stimulation. Physical and chemical stressors, e.g., cold, heat, radiation, noise, vibration, pain, immobilization, and psychological stress, can cause SNS responses [28
]. In addition, an in vivo
animal study [29
] reported stress from burn injuries and cutaneous wounds were associated with the activation of 18
F-FDG accumulation in BAT. BAT activity can be directly inhibited by beta-blockers such as propranolol, and partially reduced by diazepam, the latter probably because anxiety may also activate the SNS [30
]. BAT activation has been reported to be more frequent during the cooler seasons of the year; however, the metabolic activity of BAT depends on many factors [13
]. Consistent with previous studies [9
], our patients with activated BAT were significantly younger, leaner, more often female, had lower fasting blood sugar, and underwent 18
F-FDG PET/CT during colder outdoor temperature conditions than patients without activated BAT. Although outdoor temperature was related to the prevalence of BAT, none of the outdoor temperature parameters investigated in our study was significantly associated with the TMA of BAT. Few studies have explored the relationship between BAT activity and outdoor temperature. Consistent with our results, Kim et al. [10
] found no significant relationship between the intensity of BAT 18
F-FDG uptake and daily average outdoor temperature. A study [13
] done in Quebec, Canada, where the average outdoor temperature is substantially lower than in the tropics, showed that lower outdoor temperature was associated with an increase in the metabolic activity of BAT. We believe that the inconsistent results might be related to how low the outdoor temperature was.
Unlike patients in previous studies done in temperate zones, our patients were in tropical areas. The consistently warm outdoor temperature reduces the stimulating effects of cold environmental temperature on BAT. Univariate and multivariate analyses showed that neoplastic status was the only factor significantly associated with the TMA of activated BAT. We hypothesize that low environmental temperature is an initiator of BAT activation, and neoplastic status is important in the quantified metabolic activity of those activated BAT deposits: it is a promoter. Although we cannot conclude from the data presented that the presence of demonstrable activated BAT is a sign of cancer or the reactivation of cancer, future research on the occurrence of activated BAT and neoplastic status may be warranted.
The current study has several limitations. Because this study was retrospective, indices of the stresses associated with cancer, i.e., measurements of the HPA or SNS activities and other psychological or non-psychological factors that could influence catecholamine levels, were not well assessed. In addition, the number of patients for the analysis of the associations between the TMA of BAT and biological and environmental factors was relatively small. A larger number of patients will be needed for verification.