Research on Brown Fat Heats Up

In a sizeable advance in body fat research, three independent teams have identified a surprising energy-burning organ in healthy adults: brown fat. Splayed beneath collarbones and tucked under neck muscles, brown fat appears more active and plentiful in leaner bodies, but may be present in most people, the studies suggest.

These results overturn conventional wisdom, at least in the medical specialty that concerns itself with obesity and related diseases. “When I started my fellowship in endocrinology, I was told there is no [metabolically relevant] brown fat in adult humans,” said Aaron Cypess, HMS instructor in medicine at Joslin Diabetes Center and Beth Israel Deaconess Medical Center, and first author of one of the papers.

“All three studies have shown that adult humans have brown fat, that it’s functionally active, and that some of its activities inversely correlate with important parameters of age-related obesity,” said senior author C. Ronald Kahn, the Mary K. Iacocca professor of medicine at Joslin and HMS. “Going forward, we will be looking for ways to manipulate the activity or amount of brown fat to treat obesity and obesity-related diseases.”

The three papers in the April 9 New England Journal of Medicine come on the heels of last year’s discoveries in mice of brown fat’s closer kinship with muscle than with white fat and of the underlying molecular mechanisms that can turn immature cells into brown fat. That work was published in a related pair of Nature papers from the labs of Kahn and HMS colleague Bruce Spiegelman, the Stanley J. Korsmeyer professor at HMS and the Dana-Farber Cancer Institute (see Focus, Sept. 12, 2008).

The unusual convergence of insights into brown fat biology and its newfound metabolic significance in people have made experts nearly giddy with the possibility of a new target for combating the widespread and growing problem of obesity.

“These studies, by showing the presence and activity of brown adipose tissue in adult humans, 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,” according to an accompanying editorial in NEJM.

The findings also add a new plot twist to the dynamic tale of body fat’s role and function. Once thought to be an inert storage depot, white fat is now known to be an active organ that releases inflammatory cytokines and hormones. More recent research has revealed greater complexity in white fat with the discovery of distinctive molecular and genetic signatures intrinsic to fat deposit locations, perhaps explaining why a bulging belly is riskier to health than thick thighs (see Focus, May 16, 2008). Now comes brown fat, another story altogether.

Scientists have known about brown fat for more than 400 years. The cold-activated tissue warms the core body organs of rodents and infants. A now-classic 1981 Finnish autopsy study reported the presence of brown fat in outdoor workers, but the finding seemed to be a rare exception due to extenuating circumstances.

Brown fat derives its namesake color from the multitude of iron-rich mitochondria jam-packed into every cell. In other tissues, such as muscle, the tiny oxygen combustion units burn glucose or fatty acids to produce energy. In brown fat, mitochrondria function more as furnaces than power plants, producing heat while consuming copious calories.

“It’s almost a miraculous kind of tissue,” said Dutch physiologist Wouter van Marken Lichtenbelt, lead author of one of the NEJM studies. “In a thermoneutral environment [about 72 degrees F], brown fat sits there, and you don’t see any activity. Then in mild cold [about 61 degrees F], all of a sudden it is fully active, much more active than any other tissue.”

The genesis of all three papers came when researchers studying the molecular biology of brown fat happened to chat with colleagues in nuclear medicine. Radiologists take the presence of brown fat in people for granted.

In fact, radiologists were increasingly frustrated by splotches that obscured potential cancer nodes in three-dimensional upper-body imaging in patients. “We called it brown fat without proof,” said co-author Gerald Kolodny, chief of Nuclear Medicine at BID and an HMS associate professor of radiology.

Positron emission tomography (PET) scans detect the higher uptake of a mildly radioactive sugar solution by the more metabolically active cancerous and inflamed cells, which radiogists want to see, and by calorie-burning brown fat, which they do not want to see. Kolodny’s team had published a retrospective review of brown fat detected by PET scans in warm and cold seasons and discovered that a high-fat diet, originally designed to depress heart uptake of the radioactive sugar, also cleared away the brown adipose blotches on scans.

Cypess and his BID colleagues, including an Israel-based computer programmer, reviewed scans of 1,013 women and 959 men and developed brown fat–quantifying software, which is now freely available at the BID nuclear medicine site.

The researchers found brown fat in more women than men, but in a minority of people. Detection was also more likely in younger people, leaner older people, and cooler outdoor temperatures at time of scan. With help from colleagues at Massachusetts General Hospital and Brigham and Women’s Hospital, Cypess used molecular techniques to verify the presence of brown fat in three of five patient surgical samples from biopsies at the same location shown in the PET scans.

In one of the other NEJM studies, van Marken Lichtenbelt and his colleagues experimentally activated and detected brown fat in the PET scans of 23 out of 24 healthy young men. The third study, of five people, provided irrefutable evidence that PET scans can reveal cold-induced brown fat activity by verifying brown fat in tissue biopsies from the same people.

The findings raise hopes for targeting this natural energy-burning pathway to help fight obesity, but research on a potential clinical application has just begun in earnest. In Spiegelman’s lab, for example, Shingo Kajimura, HMS instructor in cell biology, has reconstituted new brown fat cells, implanted them in mice, and shown in a mini-animal PET scanner the implanted brown fat cells are metabolically active. Yet can they fight obesity? That answer is to come.

Cypess, Kahn, Kolodny and their colleagues have just received a Harvard Catalyst grant to build on their HMS-wide multidisciplinary research project. “This is just the beginning,” said Cypess.

Students may contact Ronald Kahn at c.ronald.kahn@joslin.harvard.edu for more information.

Conflict Disclosure: C. Ronald Kahn is an advisory board member for Sirtris, Plexxikon, FivePrime, and Dicerna, owning equity in GlaxoSmithKline, Plexxikon, and FivePrime; receiving lecture fees from Wyeth, Novartis, and Novo Nordisk; receiving grant support from the Eli Lilly Foundation; and having a pending patent in the area of stimulating brown-fat growth with bone morphogenetic proteins. Aaron Cypess receives grant support from the Eli Lilly Foundation and is the sole inventor on a pending patent application to use infrared thermography to monitor brown adipose tissue.

Funding Sources: Supported by the Clinical Investigator Training Program, Beth Israel Deaconess Medical Center–Harvard/MIT Health Sciences and Technology, in collaboration with Pfizer and Merck; grants from the National Institutes of Health; and the Eli Lilly Foundation; the content of the work is the responsibility solely of the authors.