Stat 1001 S. Weisberg, April 13, 2009

Animals have various strategies to keep warm.  When cold, most adult humans shiver, which stimulates burning calories to generate head.  Rodents, and human infants, on the other hand, don’t need to shiver, but rather use a type of fat called “brown fat”, or “brown adipose tissue” that acts like a furnace and can generate heat.  It has generally been believed that humans lose their brown fat shortly after infancy.  Several papers in the NEJM published on line April 13, 2009, however, suggest that this is not so.

Cold Study

The first article is van Marken Lichtenbelt, et al., Cold-Activated Brown Adipose Tissue in Healthy Men.  The research as sponsored by the Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, the Department of Nuclear Medicine, and the Department of General Surgery, Maastricht University Medical Center, Maastricht, the Netherlands.

“Between October 2007 and December 2008, we studied 24 healthy male volunteers; 10 were classified as lean (BMI <25), and 14 as overweight or obese (BMI, ≥25) (Table 1). The ethics committee of Maastricht University approved the protocol. All subjects provided written informed consent.”

 

 

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. During the experiment, all subjects wore standardized clothing (0.49 clo, which is a unit of measure 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.

 

Figure 1. Brown-Adipose-Tissue Activity as Assessed by PET–CT with 18F-FDG.

The results of PET–CT scanning in 9 of 24 subjects show variable physiologic uptake and distribution of 18F-fluorodeoxyglucose (18F-FDG) in adipose tissue (Panel A). The images in the top row are from lean subjects with the highest levels of brown-adipose-tissue activity (>500 kBq), images in the middle row are from lean subjects with median levels of activity, and images in the bottom row are from obese or overweight subjects with the lowest levels of activity (<100 kBq). The supraclavicular region has the greatest amount of brown adipose tissue. A PET scan in the transverse plane (Panel B) shows the areas of brown adipose tissue (e.g., arrow), and a CT scan (Panel C) confirms the areas of brown adipose tissue (arrow) according to fat density and location. Fusion of the PET and CT scans (Panel D) shows that 18F-FDG uptake is localized in fatty tissue (arrow). Comparative PET–CT scans (Panel E) reveal the patterns of 18F-FDG uptake in the same subject from the lean group after exposure to cold and under thermoneutral conditions.

 

 

 

 

“On exposure to cold, all subjects had an insulative response (a reduction of skin temperature relative to core temperature) and a metabolic response (an increase in heat production) (Table 2). Body core temperature increased slightly in response to cold exposure, with lean subjects having an increase of 0.13±0.16°C (P=0.06 for the comparison with body), and obese or overweight subjects an increase of 0.16±0.22°C (P=0.02). The mean skin temperature dropped significantly in both study groups, by 3.4±0.9°C in the lean subjects and by 3.7±0.5°C in the overweight or obese subjects. The core skin temperature gradient increased significantly during cold exposure as compared with the gradient under thermoneutral conditions (P<0.001) (Table 2). The underarm–fingertip gradient also increased during cold exposure, indicating vasoconstriction in the skin of the extremities.21 The resting metabolic rate adjusted for fat-free mass was 8.46±0.93 MJ per 24 hours in the lean subjects and 8.16±0.29 MJ per 24 hours in the overweight or obese subjects. The rate increased significantly during exposure to cold in both groups (P<0.001 for both comparisons) (Table 2), with much individual variation, ranging from 5 to 30%. No shivering was reported.”

 


Figure 4


Figure 4. Resting Metabolic Rate in Relation to Brown-Adipose-Tissue Activity.

Resting metabolic rate, adjusted for fat-free mass at thermoneutral conditions, is shown in relation to brown-adipose-tissue (BAT) activity. (With the exclusion of one outlier, indicated by a triangle, r=0.64 and P=0.001.)


Conclusions The percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.

 

The Presence of Brown Fat

Cypress, et al, Identification and Importance of Brown Adipose Tissue in Adult Humans. 

“We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery.”

            “Brown adipose tissue is present in rodents throughout life. In humans, brown adipose tissue is found primarily in infants and young children, and it has been considered to be essentially nonexistent and without physiologic relevance in adults.10 However, estimates suggest that if it were present, as little as 50 g of maximally stimulated brown adipose tissue could account for up to 20% of daily energy expenditure in an adult human.11 Despite its potential physiologic importance, methods to measure the mass and activity of brown adipose tissue in humans have been lacking. Recently, combined positron-emission tomography and computed tomography (PET–CT) has been used to identify adipose tissue with a high rate of uptake of 18F-fluorodeoxyglucose (18F-FDG) as putative brown adipose tissue.12,13,14,15,16,17 However, correlation of this tissue, detected with the use of PET–CT, with immunohistochemical evidence of UCP1 expression or metabolic state has been inconclusive.12,13,14,16,17,18,19 In this study, we analyze 18F-FDG PET–CT images in 1972 patients and present evidence for the presence of physiologically significant brown adipose tissue in adult humans.”

            “This study followed institutional guidelines and was approved by the ethics committees of Beth Israel Deaconess Medical Center and Partners HealthCare, in Boston. Because only medical records and discarded material were examined, the consent of patients was not required.”

 

 

Figure 2. Correlation between the Prevalence of Maximal Activity of Brown Adipose Tissue and Temperature, Age, Body-Mass Index, and Glucose Level.

In Panel A, for the patients with detectable brown adipose tissue, the dates on which the activity of the tissue was maximal were determined. The prevalence of maximal activity of brown adipose tissue is plotted against the mean monthly outdoor temperature in Boston after adjustment for age and sex in multivariate logistic regression. The prevalence of maximal activity of brown adipose tissue when data for men and women were combined decreased with increasing mean outdoor temperature (P=0.02). At every temperature, the probability of the detection of maximal brown adipose tissue was significantly higher for women than for men (P<0.001). In Panel B, age, body-mass index (the weight in kilograms divided by the square of the height in meters), and fasting plasma glucose level (to convert the values for glucose to millimoles per liter, multiply by 0.05551) were divided into thirds. The percentage of patients in each third who had detectable brown adipose tissue is shown, and a univariate analysis was used to assess the significance of differences in the percentages with the use of a chi-square test for linear trend.

 

Table 1. Predictors of Detectable Brown Adipose Tissue Based on 18F-FDG PET–CT Scanning.

 

Conclusions Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of 18F-FDG PET–CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.