Brown Fat-Boosting Protein Points to Safer Anti-Obesity Strategies

An international team of scientists has identified a protein that boosts the energy-burning activity of brown fat in mice, and which could feasibly lead to the development of new therapeutic approaches for treating obesity in humans. The research, headed by a team at the University of Cambridge, U.K., showed that the protein, BMP8b, effectively supercharges the function of existing brown fat (brown adipose tissue; BAT) and helps to generate new BAT. But unlike other candidates, BMP8b also stimulates the growth of new nerve cells that trigger its activity, and the formation of blood vessels that supply the BAT with oxygen and nutrients.

“There have been a lot of studies that have found molecules that promote brown fat development, but, simply increasing the amount of brown fat will not work to treat disease—it has to be able to get enough nutrients and be turned on,” said Toni Vidal-Puig, Ph.D., professor of molecular nutrition and metabolism and principal investigator at the Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, who is lead author of the team’s study published in Nature Communications.

“It’s like taking a one-liter engine out of a car and sticking in a two-liter engine in its place,” added co-author Sam Virtue, Ph.D., a researcher also from the Institute of Metabolic Science. “In theory, the car can go quicker, but if you only have a tiny fuel pipe to the engine and don’t connect the accelerator pedal it won’t do much good. BMP8b increases the engine size, and fits a new fuel line and connects up the accelerator!” The University of Cambridge team, and colleagues in the U.K., Germany, Italy, and the U.S., describe their studies in a paper titled, “Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue.”

Our bodies contain two types of fat tissue, white adipose tissue (WAT) and BAT. Both types are made up of adipocytes, but in brown fat these cells are rich in mitochondria, giving the tissue its brown color, and BAT also has a more extensive blood supply for the provision of oxygen and nutrients. The white fat that we accumulate when we become overweight stores calories, while brown fat burns energy. Just 100 g of brown fat can burn 3,400 calories per day, which could feasibly help to combat obesity.

Although adults do have some brown fat, the tissue is most abundant in newborns and in animals that hibernate and need to continue to produce heat to survive freezing temperatures. Brown fat that we do have also needs to be activated to switch on its energy-burning function. The only way to do this in adults is to put them in cold environments, which isn’t practical, or treat them with adrenergic agonists that stimulate thermogenesis, but which can cause heart attacks. Activated BAT also needs to have an adequate blood supply to provide the necessary oxygen and nutrients to the fat cells, and to be well connected to the nervous system so that it can be switched on by the brain.

Dr. Vidal-Puig’s team had previously identified BMP8b as a regulator of brown fat in the brain and in body tissues. These studies showed that brown fat didn’t function in mice that were genetically engineered to lack BMP8b. The team now reports on research in mice that overexpress BMP8b in their adipose tissue, which showed that increased levels of the protein effectively increases the function of BAT and thermogenesis. Overexpression of BMP8b in the mice was associated with browning of white fat—a process by which white fat and beige fat cells become more like brown fat—and so increased the amount of energy burnt. Importantly, this effect was evident even at even at 28˚C, a temperature at which the brain wouldn’t normally stimulate the process.

“Our data strongly support the local remodeling effect of BMP8b in WAT given that active remodeling is maintained in mice born and housed at 28 °C,” the authors write. “This is an important experimental detail, given that 28°C corresponds to the environmental temperature at which the SNS (sympathetic nervous system) input is at a minimal level … Our results have shown that beige cells, despite their early development and apparent disappearance during adulthood, retain their hyper-responsiveness to adrenergic stimulation in adult mice, behaving as ‘dormant’ beige cells.”

High levels of BMP8b also rendered BAT more sensitive to adrenergic signals from the nervous system, which could mean that any future BMP8b-derived drugs designed to stimulate thermogenesis may be active at lower, safer doses than current adrenergic agonist compounds. And encouragingly, but unexpectedly, the studies showed that BMP8b stimulated the formation of blood vessels and nerves into the BAT.

“This is the first study identifying adipocyte-secreted BMP8b as a potential regulator of neuro-vascular processes, essential to couple adrenergic responsiveness, adipose tissue remodeling, and efficient thermogenesis,” the team commented. Although much more research will be required to start to translate the findings in mice into clinically relevant results, the researchers suggest that “it should be feasible to control the efficient coordination of adipocyte thermogenesis, angiogenesis, and innervation.”

They conclude, “the evidence that BMP8b-mediated signaling may couple browning and optimization of the supporting neuro-vascular network provides the rationale for a new and safe approach to the treatment of the obese patient, addressing the problem of previous anti-obesity therapy-based adrenergic stimulation, discontinued because of associated hypertension and/or tachycardia.”