New approach to treating obesity: energy-burning brown fat?

Brown fat counteracted obesity in new study.

New data suggest that the PR domain containing 16–C/EBP-beta complex initiates brown fat formation from myoblastic precursors and may provide opportunities for the development of new therapeutics to counteract obesity and type 2 diabetes.

“Since brown fat cells have very high capacity to dissipate excess energy and counteract obesity, engineered brown adipose tissue has a very high potential for treating obesity,” researcher Shingo Kajimura, PhD, instructor in cell biology at Dana Farber Cancer Institute, said in a press release. “We are currently working on this.”

A group of researchers at Dana Farber, Harvard Medical School and Beth Israel Deaconess Medical Center identified both parts of a molecular “master switch” that normally causes some immature muscle cells in the embryo to become brown fat cells, also known as brown adipose tissue. Using this switch, researchers found that PRMD16 works in tandem with the C/EBP-beta and were able to manipulate it to force other types of cells in the laboratory to produce brown fat.

The researchers transplanted engineered brown adipose tissue into adult mice to increase their innate stores of brown fat and into human skin cells isolated from foreskins removed from newborns during circumcision. Tests showed that the brown fat transplants were burning caloric energy at a high rate — energy that would have been otherwise stored as fat in white adipose tissue.

The findings were published online in Nature.

Brown adipose tissue

White fat cells store excess caloric energy in the diet, which typically piles up in the body — particularly in the abdomen and thighs. The accumulated fat content in overweight people puts stress on white cells, which in turn signal inflammation in body organs and the circulatory system, creating risk for heart disease and diabetes.

Brown fat, on the other hand, works in an opposite fashion. Brown fat cells are equipped with a large supply of mitochondria to use oxygen to burn sugar from the diet to generate heat rather than store the energy as fat.

Brown fat evolved to protect animals from cold conditions and prevent obesity. Until April 2009, data suggested that brown fat disappeared and was not found in adults. However, researchers at the University of Goteborg in Sweden reported that some brown fat tissue persists in adults. Studies using modern positron emission tomography scanners have revealed unexpectedly large amounts of brown fat in the neck and chest areas.

In the current study, the researchers did not test whether the extra brown fat protected the mice from becoming obese.

Brown fat in humans

These results “give a lot more credence” to efforts to manipulate the brown fat switch as a potential means for treating people with obesity and diabetes, Bruce Spiegelman, PhD, professor of cell biology, Harvard Medical School, said in a press release.

One strategy would be to remove some brown adipose tissue from the patient, add the PRDM16-C/EBP-beta switch, and return it to the patient where it could manufacture additional brown fat. A more conventional possibility would be to administer a drug to the patient that would ramp up production of brown fat without the need for a transplant.

“If we can find a hormone that does that, it’s reasonable to think that it might provide a direct anti-obesity treatment,” Spiegelman said.

In April, researchers reported that the amount of brown adipose tissue in humans was inversely correlated with BMI, a finding that suggests that brown fat could play an important role in protecting against age-related obesity. Using 3,640 consecutive F-fluorodeoxyglucose PET and CT scans, researchers identified brown adipose tissue in 7.5% of women and 3.1% of men. The most common location for brown tissue was the cervical-supraclavicular depot (12.3 g in women; 11.6 g in men). Brown tissue was detected most in people aged younger than 50 years, the least obese, those with the lowest fasting plasma glucose levels, those not using beta-blockers and never-smokers.

According to the researchers, further research is being conducted to see what happens when brown fat cells are implanted into obese mice. – by Jennifer Southall

Cypess AM. N Engl J Med. 2009;360:1509-1517.

Kajimura S. Nature. 2009;doi:10.1038/natureo8262.

The findings by Kajimura and colleagues represent a very important step for those looking to treat human obesity by utilizing the calorie-burning power of brown fat. Spiegelman’s team identified two particular proteins — PRDM16 and C/EBP-beta — that when working together are important for pushing precursor cells to become oxygen-consuming brown adipocytes. They then performed proof-of-concept studies to show that a mass of brown fat could be made ex vivo and then transplanted into nude mice to make a glucose-using brown fat tissue. While there are several additional steps that would have to be made before these methodologies could be developed into a safe therapy to treat obesity, it is very encouraging.

– Aaron Cypess, MD, PhD

Instructor, Harvard Medical School, Research Associate and Staff Physician at Joslin Diabetes Center