A team of researchers led by scientists at the University of California, Berkeley, has identified a decades-old oral compound that produced substantial weight loss in obese mice.
Rather than suppressing appetite, the compound appears to boost energy expenditure, according to a study published in Science Advances.
The molecule, known as TOFA, reduced the mice’s body weight by an average of 18% without changing how much they ate or causing a statistically significant loss of lean mass.
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While popular injectable weight-loss medications such as semaglutide can produce substantial weight loss partly by reducing food intake, some patients experience gastrointestinal side effects and loss of lean mass.
Studies have also found that people often regain a significant amount of weight after stopping treatment.
Preserving muscle during weight loss remains one of the greatest clinical hurdles in obesity medicine, according to experts.
“Muscle mass is really important for our function during the day. It helps fight the effects of aging,” Dr. Leslie Pristas, a bariatric surgeon and owner of Best Life Bariatrics and Medical Weight Loss in Northeast Ohio, told Fox News Digital.
“Building muscle is really hard. It takes a really long time. So if we can avoid having muscle loss while we’re having weight loss, that’s going to be so much better.”
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Instead of primarily targeting appetite, TOFA acts inside cells, according to the researchers. It blocks enzymes involved in the production of lipids, including fats such as triglycerides, while also activating cellular receptors that turn on genes involved in fat burning and energy production.
Treated mice burned up to 18% more energy under room-temperature and mildly warm conditions, without becoming less active or developing a dangerous increase in body temperature.
When the researchers combined TOFA with existing obesity drugs such as semaglutide or tirzepatide, the combination treatments produced greater reductions in body weight and improvements in blood sugar, insulin and triglyceride levels than either drug alone.
Mice treated with TOFA maintained body weights close to control levels after treatment ended, while mice previously given semaglutide began rapidly regaining weight.
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Pristas urged caution against assuming that any single medication could permanently prevent post-treatment weight gain.
“Obesity is super complex,” she said. “There’s not just one mechanism by which everyone gains weight or even a single person gains weight. There are a lot of overlapping factors.”
“Once we have extra weight on our body, that kind of becomes where our body thinks we’re supposed to be. That becomes our body’s weight set point,” she noted, adding that if someone stops a medication abruptly, the body may then work to return to its previous weight.
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The compound also showed promise in mouse models for metabolic dysfunction-associated steatohepatitis (MASH), a form of fatty liver disease. Mice given TOFA had less liver fat, inflammation and fibrosis (scarring).
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TOFA achieved these liver benefits without increasing triglyceride levels in the blood, the researchers noted. Some similar metabolic drugs have caused triglycerides to rise, creating potential cardiovascular and other health concerns that have complicated their development.
The authors emphasized that all the animal experiments involved male mice. Future studies will need to determine whether TOFA produces similar results in female animals.
The drug has not yet been tested in people, so researchers still don’t know what dose would be appropriate, whether it is safe to use over long periods, or whether it could cause subtle toxicities or other safety problems.
Pristas emphasized that early mouse data must be weighed carefully against potential hidden side effects in humans.
“If it sounds too good to be true, it’s probably too good to be true,” she said.
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“When you’re talking about manipulating our bodies’ manufacturing or processing of lipids, it’s complex. And so there can be downstream effects that we don’t want. That’s where we can’t get too excited.”
However, the expert said the treatment could eventually benefit people, either on its own or in combination with another therapy.
The study authors disclosed that several researchers are co-founders, officers or equity holders in ReRx Therapeutics, a company with an agreement giving it the option to develop UC Berkeley’s TOFA-related discovery.
