Brown Fat Activity Associated With Body Mass Index in 3 New Studies

Deborah Brauser

April 10, 2009

April 10, 2009 — Brown adipose tissue is not only present in adult humans, but its activity can be significantly influenced by factors such as body mass index (BMI) and, to a lesser degree, temperature and sex, according to results of 3 new multinational studies reported in the April 9 issue of the New England Journal of Medicine.

"Studies in animals indicate that brown adipose tissue is important in the regulation of body weight," write Wouter D. van Marken Lichtenbelt, PhD, from the Department of Human Biology at the Nutrition and Toxicology Research Institute Maastricht at Maastrict University Medical Center, the Netherlands, and colleagues from the first study. However, "Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants. Although several early anatomical studies suggested that brown adipose tissue is present in adult humans, its physiologic relevance was believed to be marginal for most."

In all 3 of the new studies reported in the article, investigators set out to evaluate not only the presence of this tissue but also which factors can affect its activity.

Brown Fat and Body Composition/Energy Metabolism

In the first trial, Dr. van Marken Lichtenbelt and colleagues studied the activity of brown adipose tissue in relation to body composition and energy metabolism.

"Cold-induced thermogenesis and diet-induced thermogenesis have recently been shown to be related, suggesting that they have a similar underlying mechanism," write the study authors. In addition, "Some [previous] studies indicate that brown adipose tissue is related to the [BMI,] and others do not."

In this study, investigators examined the presence, distribution, and activity of this tissue in 24 healthy men aged 18 to 32 years under both thermoneutral conditions (22°C) and mild cold exposure (16°C) between October 2007 and December 2008. Of these participants, 10 were classified as lean (BMI < 25 kg/m2), and 14 were considered overweight or obese (BMI ≥ 25 kg/m2).

Tissue activity was determined with postitron-emission tomography and computed tomography (PET-CT) scanning with F-fluorodeoxyglucose (F-FDG). Body composition was measured with dual-energy X-ray absorptiometry and energy expenditure with indirect calorimetry. Brown adipose tissue was activated by a standardized cold-exposure test. In a climate chamber, the participants rested in a supine position under thermoneutral conditions for 1 hour, followed by mild cold for 2 hours.

At the end of the study, brown adipose tissue activity was observed in 23 (96%) of the 24 subjects during cold exposure, but not under thermoneutral conditions. Although the level of activity was highest in the supraclavicular region, other sites with activity were also evident.

In addition, nonlinear regression analysis showed that the activity of whole-body brown adipose tissue was negatively correlated with BMI (r, −0.60; P = .002) and percentage of body fat (r, −.60; P = .001), with the mean activity significantly lower in the overweight or obese subjects than in the lean subjects (P = .007).

The investigators write that one reason for the high incidence of activity in their study could be the relatively young age of the subjects. "It is likely that the amount of brown adipose tissue decreases with age, although no relation between [this] tissue activity and age was observed in our study."

They conclude, "[In this study,] 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 activity 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."

Imaging Study for Presence of Brown Fat

In the second trial, US investigators analyzed F-FDG PET-CT images for the presence of physiologically significant brown adipose tissue in adults.

"[Previous] estimates suggest that if it were present, as little as 50g of maximally stimulated brown adipose tissue could account for up to 20% of daily energy expenditure in an adult human," write Aaron M. Cypress, MD, PhD, MMSc, from the Research Division of the Joslin Diabetes Center, Boston, Massachusetts, and colleagues. "Despite its potential physiologic importance, methods to measure the mass and activity of [this] tissue in humans have been lacking."

Wanting to study the correlation of this tissue with immunohistochemical evidence of uncoupling protein 1 (UCP1) expression or metabolic state, the investigators analyzed 3640 consecutive F-FDG PET-CT whole-body scans of 1972 adult patients (1013 women, 959 men) for the presence of substantial depots of putative brown adipose tissue. They defined these depots as collections of tissue more than 4 mm in diameter, having the CT density of adipose tissue (−250 to −50 Hounsfield units) and maximal standardized uptake values of F-FDG of at least 2.0 g/mL, 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.

The investigators identified substantial depots of brown adipose tissue in a region extending from the anterior neck to the thorax, with tissue from this region having UCP1-immunopositive multilocular adipocytes.

Positive scans were seen in 76 women (7.5%) and 30 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P < .001). Women also had a greater mass of brown adipose tissue and higher F-FDG uptake activity. The median amount of detectable brown adipose tissue was 11.6 g (range, 0.5 – 42.0) in men and 12.3 g (range, 1.1 – 170.0) in women, with the most common location for the tissue detected in all patients in the cervical-supraclavicular depot.

In addition, the probability of the detection of brown adipose tissue was inversely correlated with years of age (P < .001), outdoor temperature at the time of the scan (P = .02), and beta-blocker use (P < .001). Among older patients, the detection was correlated with BMI (P = .007).

Study limitations include the scanning of the patients in an unstimulated state, as PET-CT identifies only brown adipose tissue with increased metabolic activity. In addition, the study authors write, "Dietary fuels, such as fatty acids, and some drugs can alter F-FDG uptake and PET-CT can detect [this] tissue only if a sufficient number of brown adipocytes are aggregated in a given anatomical site."

They conclude, "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 F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with [BMI], especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism."

Temperature-Related Activation of Brown Fat

In the third small trial, investigators from Finland and Sweden used PET scans to evaluate the activation of brown adipose tissue by exposure to cold temperatures in 5 healthy patients.

"It is believed that this tissue regresses with increasing age and is completely lost by the time a person reaches adulthood," write Kirsi A. Virtanen, MD, PhD, from the Turku PET Center at the University of Turku, Finland. "However, the capacity to produce [this] tissue in adulthood has been shown in patients with catcholoamine-secreting tumors such as pheochromocytomas and paragangliomas, in whom distinct brown-adipose-tissue depots develop." They write that when diagnosing neoplasms and their metastases with a combination of PET-CT and glucose analogue F-FDG, the results can be confounded by a high glucose uptake in the supraclavicular tissue. In addition, the localization of the F-FDG in adipose tissue on CT images occurs more often during winter months than in the summertime.

So each of the 5 participants in this study underwent 2 PET-CT F-FDG scans — one during cold exposure and the other during warm conditions. Biopsy specimens of tissues were obtained from the first 3 consecutive subjects.

Results showed that cold-induced glucose uptake was increased by a factor of 15 (P = .0005) in supraclavicular adipose tissue in all 5 patients compared with an increase by a factor of 4 in white adipose tissue (P = .01).

The tissue biopsy specimens showed the presence of the marked RNA markers of brown adipose tissue of UCP1 and deiodinase, iodothyronine, type 2 (DIO2). "This finding is of interest because it appears that DIO2 is expressed by brown adipocytes in order to make triiodothyronine available to sustain the elevated metabolism of brown adipose tissue," write the study authors.

In addition, the tissue expressed substantial levels of UCP1 protein and cytochrome c and was characterized by numerous multilocular, intracellular lipid droplets.

"On the basis of the data presented here and previous findings regarding the metabolism of brown adipose tissue, we speculate that activation of [this] tissue by cold exposure may be important in terms of energy expenditure in humans," the study authors conclude. "We suggest that the presence of [this] tissue in normal adults is worthy of further study and speculate that this tissue might provide a pharmacologic target, given the current obesity pandemic."

Brown Fat a "Natural Target"

In an accompanying editorial, Francesco S. Celi, MD, from the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, writes that interventions designed to increase energy expenditure are relatively limited. "Brown adipose tissue represents a natural target for the modulation of energy expenditure."

"The common message from these studies is that brown adipose tissue is present and active in adult humans and its presence and activity are inversely associated with adiposity and indexes of the metabolic syndrome," writes Dr. Celi.

He writes that a major shortcoming of the studies "is the lack of direct correlation between brown-adipose-tissue activity and cold-stimulated changes in energy expenditure. This could be secondary to the inability of the PET-CT technique to measure the activity of small nests of brown adipose tissue."

However, "Taken together, these studies point to a potential 'natural' intervention to stimulate energy expenditure: turn down the heat and burn calories." Noting that this strategy is obviously an oversimplification, Dr. Celi concludes, "Nonetheless, these studies...are a powerful proof of concept that this tissue might be used as a target for interventions, pharmacologic and environmental, aimed at modulating energy expenditure."

The authors of the first and third studies have disclosed no relevant financial relationships. There were several sources of support for the second study, and several of its authors have disclosed financial relationships. A complete list of support and disclosures is available in the original article. There were also several sources of support for Study 3. The complete list of support and disclosures also is available in the original article. Dr. Celi has disclosed no relevant financial relationships.

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