HMS researchers are unlocking the secrets of a hormone known to stimulate weight loss and improve glucose metabolism.
Harvard Medical School researchers at Joslin Diabetes Center have discovered that a hormone long associated with weight loss and improved glucose metabolism is linked to activation of calorie-burning brown fat. This finding could have implications for production of new medications for type 2 diabetes and obesity.
The results are published in the January issue of the Journal of Clinical Investigation in a paper titled “Interplay between FGF21 and Insulin Action in the Liver for the Regulation of Metabolism.”
For the past decade, the hormone FGF21 (fibroblast growth factor 21) has been known to play a role in metabolic regulation. Its mechanism of action, however, remained unidentified.
“So what we were interested in learning is how does FGF21 both stimulate weight loss and improve glucose metabolism,” said corresponding author on the paper C. Ronald Kahn, Mary K. Iacocca Professor of Medicine at HMS and chief academic officer at Joslin.
“And this study shows that one big factor in this is the ability of FGF21 to stimulate what’s called browning of white fat. That is where the white fat becomes more energetically active and begins to burn energy rather than store energy.”
In 2009, Joslin researchers showed that brown fat exists in humans and burns calories to produce heat. White fat can act in a similar manner when stimulated, a process known as “browning.”
Determining stimulation mechanisms can provide researchers with a first step toward using brown fat as a treatment for obesity and type 2 diabetes.
FGF21 is secreted from the liver, prompting Kahn and colleagues to question if its metabolic-related activity depended on molecular interactions within the liver tissues. They tested their hypothesis using insulin-resistant animal models created through two different methods: feeding the mice a high-fat diet or knocking out the insulin signaling in the mice’s liver tissues.
The investigators then introduced FGF21 to both model groups continuously for two weeks via an inserted pump. During that time, they monitored weight, blood glucose levels and lipid levels. After the two weeks ended, they analyzed the liver tissue.
“What we found was that even without insulin signaling in the liver, FGF21 could still improve glucose metabolism,” said Kahn.
To determine that the improvements were due to the browning of white fat, rather than the activation of brown fat, they removed the animals’ brown fat pads.
“So, in those animals, where most of the brown fat is removed, FGF21 still works on the remaining white fat because of browning,” Kahn said.
FGF21 also regulates lipid metabolism, and the researchers determined that that process is dependent on functioning insulin signaling in the liver.
Proving that FGF21 activates the browning of white fat is a large step forward in understanding the process of how variations of brown fat assist in metabolic regulation.
Identifying this hormone as a major player in this activation has implications for the eventual creation of a brown fat-stimulating drug.
“As with any new drug or hormone, of course, we need to learn not only its good effects, but also any potential side effects,” said Kahn. “And I think that’s where a lot of the effort is now … by pharmaceutical companies.”
In addition to its drug potential, Kahn thinks this discovery is interesting from a basic biology point of view.
“FGF21 wasn’t even known to exist until 10 years ago, and now we know it is a new circulating hormone that is regulated in feeding and fasting,” he said.
“And I think that this is another piece of evidence that we don’t understand all there is to know yet about metabolic regulation even though people have been studying it for literally hundreds of years.”