It’s a conundrum well-known to scientists and dieters alike: When one loses weight, the body’s metabolism slows, making it harder to keep the pounds off even with continued calorie restriction. But despite being documented for more than 50 years, researchers haven’t yet figured out a way to outsmart the phenomenon, known as adaptive thermogenesis.
“We know people are very good at losing weight in the short term,” Gregory Steinberg, Ph.D., a researcher at McMaster University, told Fierce Biotech Research in an interview. “But if you lose 10% of your body weight, your metabolism will slow down by 200 to 300 calories a day. The mechanisms behind that aren’t really well understood.”
Steinberg and his lab have unlocked new knowledge in the quest for the ultimate solution: A weight loss drug that doesn’t just help patients lose pounds, but does so without slowing their metabolism. In the results of a new study published June 27 in Nature (sponsored in part by Novo Nordisk), his team of international collaborators described how they discovered that the protein growth/differentiation factor 15, or GDF15, induces weight loss by stimulating muscle cells to burn more energy. Their findings also shed light on the mystery of how losing weight drives down one’s metabolism.
While GDF15’s potential to induce weight loss has been established in preclinical models for a while—drugs that stimulate its receptor, GFRAL, have even made it to clinical trials—this is the first time a research team has characterized its mechanism of action. Steinberg and his team were building on previous work that suggested the appetite-suppressing effects of the diabetes drug metformin depended on GDF15, levels of which increased in response to the drug. But back then, it wasn’t clear how or why.
“This was a really bizarre finding to us because when we looked at what the heck GDF15 is and why it was going up, we saw that it was a biomarker indicating that, basically, you were going to die,” Steinberg recalled. Indeed, high GDF15 levels are associated with cancer, heart attacks, strokes and death in general—the opposite of what you’d expect to see from taking metformin, which some research has linked to longevity.
As the scientists were scratching their heads, new papers began to emerge showing a link between GDF15 and weight loss. The molecule appeared to be responsible for appetite suppression in cancer patients—a quality that Big Pharma was already eyeing, according to Steinberg.
But he and his team wondered if GDF15 might be doing something more.“We were really intrigued by the idea that it might be controlling metabolism independently of its impact on appetite,” he said.
The researchers took two groups of mice, injected one with the unmodified GDF15 protein, and then over the course of two weeks fed them according to what’s called caloric matching or pair feeding: However much the treated group ate, the untreated group was fed the same amount. As expected, both groups lost weight—the same amount, in fact, about 5% of their starting body weight.
“This was exactly what other groups had shown before, which led to the conclusion that GDF15 was primarily causing weight loss by suppressing appetite,” Steinberg explained.
But unlike in earlier studies, his team extended the experiment out another four weeks. Over that period, weight loss plateaued in the untreated group in spite of their still-restricted diet. Meanwhile, the treated group continued to shed kilograms, with the group that received a lower dose of the drug dropping to about 85% of their starting weight and the one that received a higher dose falling to 76%.
What the researchers observed in the untreated mice “is consistent with dieting—you can stick with the same diet, but you don’t just keep losing weight,” Steinberg said. “Eventually, your metabolism slows down and the weight loss doesn’t happen at the same rate.”
That wasn’t the case for the mice treated with GDF15, however, indicating that something must be keeping their metabolism revved. Experiments on genetically-altered mice lacking the GDF15 receptor in the brain confirmed that the molecule’s presence there was essential for energy expenditure, but they didn’t explain the connection between the brain and the body.
That sent the team on a bit of a hormone goose chase. Was the protein-altering thyroid hormone levels? Nope. Cortisol? Not that, either.
A light bulb began to glow when the researchers found that mice with a gene mutation that impaired sympathetic nervous system (SNS) activity didn’t lose weight after being injected with GDF15. At first, the researchers thought SNS stimulation might be activating a process called futile cycling in brown fat. Futile cycling is when two metabolic pathways run simultaneously, producing and reusing each others’ metabolites, with no net product other than burned energy.
“But we looked at this for over a year and found absolutely no evidence that it was increasing energy burning [in brown fat],” Steinberg recalled. “And then we got to thinking, ‘Well, maybe it’s muscle.’”
Additional studies confirmed that idea. By stimulating the sympathetic nervous system, GDF15 was upregulating calcium release in the muscle. The muscle cells were using it up through futile cycling, releasing energy in the process, Steinberg explained.
“[The process] required more ATP to get that calcium back under control,” he said. “And of course, if you’re using more ATP, then you need to burn more calories to keep those levels constant.” The effects of this were apparent when the researchers compared the muscle mass of GDF15-treated mice with the ones on a calorie-restricted diet alone. As expected, the untreated mice lost muscle function—dieting causes you to lose not just fat, but muscle mass. But the ones in the GDF15 group preserved it.
This is a key difference from GLP-1 agonists, Steinberg noted. Rapid muscle loss is one of the maligned side effects of drugs like Ozempic and Wegovy; in the STEP1 trial on semaglutide, a drop in lean muscle mass accounted for nearly 40% of total weight loss. The same results were seen in the SUSTAIN 8 trial, which also found that 40% of weight loss could be contributed to shrunken muscle mass, even with lower doses.
“This is really important because this is one of the things that people don’t like about the GLP-1 receptor agonists,” Steinberg said. “But it seemed like GDF15 was maintaining muscle function better than if you just restricted the calories.”
It’s unclear right now how GDF15 will fit into the wider world of weight loss drugs. Clinical trials on modified forms of the protein have produced disappointing results Lilly, for instance, reported in February that a phase 1 test of its long-acting GDF15 receptor agonist showed that despite attenuating appetite and being well-tolerated, the drug had little effect on participants’ weight.
“These results demonstrate that agonism of the [GDF15-GFRAL receptor system] can modulate energy balance in humans, though the decrease in body weight is surprisingly modest, suggesting challenges in leveraging the GDF15 system for clinical weight loss applications,” the researchers concluded.
Those lackluster results aren’t necessarily a reason to stop pursuing GDF15 as a weight loss aid, Steinberg said, especially given what scientists are learning about its mechanism of action. It could be that the best results will come from combining GDF15 and GLP-1 receptor agonists, or that unmodified GDF15 itself is the ticket to efficacy in humans. No one so far has tried injecting people with native GDF15, as far as Steinberg knows.
And in any case, scientists spent decades trying to develop a GLP-1 agonist that could work for weight loss in humans, he pointed out.
“The initial GLP-1 receptor agonist didn’t induce this huge weight loss that we see today—it took 20 years of refining them to get where we are now,” Steinberg said. “It didn’t just happen overnight. It’s easy to say that this is just a mouse study that didn’t translate, but I think it’s too early to say that.”
For his team, there are a couple of items next up on the to-do list. One is animal studies putting weight loss drugs with GDF15 to see whether combination therapies might be effective. Another is human research analyzing how levels of the protein change after the pounds come off.