Cold-Activated Brown Adipose Tissue in Healthy Men
T here is evidence that stimulating a d a p t i v e t h e r m o g e n e s i s , d e f i n e d a s t h e f a c - u l t a t i v e h e a t p r o d u c e d i n r e s p o n s e t o c o l d and diet, might serve as a means of preventing or treating obesity1; thus, it is of interest to under- stand the mechanisms underlying adaptive thermo- genesis. We previously reported that cold-induced thermogenesis in the absence of shivering accounts for an average of 11.8% of the resting metabolic rate, with high individual variation.2 Individual differences in energy expenditure can have large, long-term effects on body weight.3 Several prospec- tive studies have shown that a relatively low en- ergy expenditure predicts a gain in body weight.4,5 Hence, adaptive thermogenesis may be an attrac- tive target for antiobesity therapies.
Cold-induced thermogenesis and diet-induced thermogenesis have recently been shown to be related, suggesting that they have a similar un- derlying mechanism.6 In small mammals, brown adipose tissue serves as a thermogenic organ, in which mitochondrial respiration is uncoupled from ATP production (through the action of uncoupling protein 1 [UCP1]) to dissipate energy. Although several early anatomical studies suggested that brown adipose tissue is present in adult humans,7-9 its physiologic relevance was believed to be mar- ginal for most.9,10 In the past few years, however, studies conducted for other reasons that made use of integrated positron-emission tomography and computed tomography (PET–CT) indicated that brown adipose tissue is occasionally present and active in adult humans,11-14 with the preva- lence ranging from 2.5%11 to 45%.15 Some studies indicate that brown adipose tissue is related to the body-mass index (BMI),15,16 and others do not.12,17
We systematically examined the presence, dis- tribution, and activity of brown adipose tissue in healthy volunteers in relation to body composition and energy metabolism. The activity of brown adi- pose tissue was assessed with the use of PET–CT scanning with 18F-fluorodeoxyglucose (18F-FDG), body composition with dual-energy x-ray absorp- tiometry (DEXA), and energy expenditure with indirect calorimetry. Brown adipose tissue was activated by a standardized cold-exposure test.
Subjects and Procedures
Between October 2007 and December 2008, we studied 24 healthy male volunteers; 10 were clas-
sified as lean (BMI [the weight in kilograms di- vided by the square of the height in meters], <25), and 14 as overweight or obese (BMI, ≥25) (Table 1). The ethics committee of Maastricht University approved the protocol. All subjects provided writ- ten informed consent. In addition, a female pa- tient provided written informed consent for the removal of samples of brown adipose tissue and white adipose tissue during surgery for multinod- ular goiter.
Subjects were studied in the morning, from approximately 9 a.m. to 1 p.m., after an overnight fast beginning at 10 p.m. the night before. Dur- ing the experiment, all subjects wore standard- ized clothing (0.49 clo, which is a unit of mea- sure for the insulating properties of clothing). In a climate chamber, the subjects rested in a supine position under thermoneutral conditions (22°C) for 1 hour and were then exposed to mild cold (16°C) for 2 hours. After 1 hour of exposure to cold, the PET tracer 18F-FDG was administered intravenously, and scanning was performed after the second hour of exposure to cold. Three sub- jects with relatively high levels of brown-adipose- tissue activity underwent an additional PET study in thermoneutral conditions in order to determine whether brown adipose tissue was activated only after cold exposure.
The PET–CT scanning protocol (Gemini TF PET–CT, Philips) included confirmation of the serum glucose level and the intravenous injection of 2 mCi (74 MBq) of 18F-FDG. Subjects rested comfortably, with the head, neck, and shoulders supported from the outset of the experiment until imaging began. Imaging was performed in three- dimensional mode, with emission scans of 6 min- utes per bed position. Six to seven bed positions per subject were needed to cover the areas where brown adipose tissue is usually found. Imaging started with a low-dose CT scan (30 mAs), imme- diately followed by a PET scan. The scanner was equipped with time-of-flight electronics, which allows the use of a relatively low amount of ra- dioactivity (2 mCi). The resulting total radiation dose from the low-dose CT scan and the injected radioactive tracer was approximately 2.8 mSv. The CT scan was used for attenuation correction and localization of the 18F-FDG uptake sites. Both image sets were reconstructed in transaxial, coro- nal, and sagittal images with a slice thickness of 4 mm. Two nuclear-medicine physicians in- terpreted the PET–CT images using PMOD soft-
n engl j med 360;15
april 9, 2009
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