Miriam E. Tucker
May 24, 2021
A peripherally acting substance that boosts energy expenditure and reduces fat mass has the potential to become an obesity treatment that doesn’t produce cardiovascular or psychiatric side effects, scientists say.
The agent, BIBO3304, is a selective antagonist of the neuropeptide Y1 receptor, which is elevated in the fat tissue of individuals with obesity, resulting in reduced fat accumulation. It was originally developed more than 25 years ago by scientists at Boehringer Ingelheim, who had thought it would reduce appetite by targeting Y1 receptors in the brain. But when it didn’t cross the blood–brain barrier as an oral drug, the company abandoned it.
Now a series of experiments by Chenxu Yan, of the Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, New South Wales, Australia, and colleagues have shown that “BIBO” works directly on Y1 receptors in the periphery to turn fat-storing white fat cells into heat-generating brown-like fat tissue, thereby enhancing energy expenditure.
The data were published online May 11 in Nature Communications.
“Rather than just having the cells store fat, we change their characteristics so that most of the excess energy gets burned and produces heat instead of being stored as fat. BIBO programs the cell toward a more heat-producing cell rather than a fat-storing cell,” study coauthor Herbert Herzog, PhD, of the Garvan Institute, told Medscape Medical News.
Importantly, he said, the lack of effect on the brain that caused the drug’s initial developer to abandon it turns out to be a positive.
“As we looked at fat specifically, and we didn’t want to have any interference with the brain, this seems to work out as a real advantage…It has the desired effect of blocking fat accumulation but has the enormous benefit of not interfering with any brain function. That’s why so many of the obesity drugs that were on the market were taken off, because of the side effects they caused in the brain on mood and cardiovascular control. It’s a completely different ball game.”
The problem now, he said, is that because BIBO is off-patent no pharmaceutical company is currently willing to invest in its development as a peripherally acting weight-loss drug, despite its potential advantages.
“We’re trying to find some interested party to help us get this to the clinical setting. We’re basic scientists. We need big money. We can do small-scale studies to get proof of principle. Hopefully, if that’s interesting, some bigger company will come along,” said Herzog.
In the series of studies, investigators fed genetically inbred mice a high-fat, high-sugar diet while giving BIBO to half of them. Over 8 weeks, the mice given BIBO had 40% less gain in fat mass compared to those overfed without the drug, despite them all eating the same amount.
Using a noninvasive infrared camera to measure skin surface temperature above brown adipose tissue, they found that the temperature was significantly increased with BIBO, independent of the weight of the brown fat.
This suggests that the thermogenesis of the brown fat is significantly contributing to whole-body energy expenditure. “With the drug, the mice have far greater energy expenditure measured by heat production,” Herzog explained.
In vitro experiments showed that Y1R blockade by BIBO induced “beigeing” of white fat deposits into more heat-producing brown fat. The body temperature increase is about 0.1-0.2ºC. “That’s a tiny amount, but it actually requires quite a lot of energy,” he said.
Experiments using fat tissue taken from obese and normal-weight humans showed the same thermogenesis with BIBO. “It’s such a fundamental process you wouldn’t expect it to differ. The same mechanism is even found in flies and primitive worms,” he noted.
Previously, Herzog and colleagues found that blockade of the neuropeptide Y1 receptor also increases bone mass in mice.
“It’s a modest effect, but there’s nothing out there at the moment that really improves bone mass. If you can stop osteoporosis that’s a benefit on its own,” he said.
Now they hope to study BIBO’s vasodilatory properties as a potential treatment for hypertension, if they get the funding.
Herzog is hopeful, as obesity, osteoporosis, and hypertension are all chronic conditions. “Having one drug that benefits them all would surely be of interest to clinicians and drug companies,” he observed.
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