The 1970s drug that turbocharges fat jabs - and cuts the side-effects

Could the next generation of weight-loss drugs help you shed fat without suppressing appetite – and prevent muscle loss?That’s the possibility raised by an experimental compound called TOFA which, unlike drugs such as Wegovy and Mounjaro, appears to make the body burn more energy rather than simply encouraging people to eat less.Better still, early tests suggest combining TOFA with existing weight-loss jabs could dramatically boost their effects, allowing them to work at lower doses. TOFA is a manmade compound created in the 1970s after scientists found that certain synthetic chemicals could lower fats in the blood.They modified these chemicals to produce TOFA, designed to reduce the body’s production of fats.However, it was never developed into a medicine and instead remained largely a laboratory research tool.But now researchers at the University of California, Berkeley, have taken another look at the old compound and discovered that it has another unique effect: it makes cells burn fat for energy.Unlike existing weight-loss drugs, TOFA does not mimic a natural hormone. Instead, it acts on several pathways involved in fat metabolism. It blocks enzymes involved in making new fat, while also activating two proteins that switch on genes involved in burning fat and producing energy.In recent research published in Science Advances, obese mice given the drug lost around 18 per cent of their body weight over four weeks without eating less. Remarkably, almost all the weight they lost was fat, with no significant loss of lean tissue, including muscle. An experimental compound called TOFA appears to make the body burn more energy rather than simply encouraging people to eat less, unlike drugs such as Wegovy and MounjaroThis could be important because preserving muscle while losing fat is a major challenge with weight loss generally. Indeed, around a fifth of the weight lost with existing drugs is muscle.In a second experiment, the US researchers tested whether TOFA could be combined with existing weight-loss drugs.The mice were given low doses (around 20 times lower than the doses given in obesity trials) of semaglutide – the drug in Ozempic and Wegovy – or tirzepatide, the drug in Mounjaro, alongside TOFA. After 24 days, mice given the new drug alone had lost 8.7 per cent of their body weight, compared with 6.7 per cent with semaglutide alone and 4.5 per cent with tirzepatide.But the combinations produced much larger losses: 26.9 per cent with TOFA plus semaglutide; and 37.1 per cent with TOFA plus tirzepatide. Furthermore, the mice given this combination lost 26 per cent of their body weight after just ten days, prompting the researchers to halve the doses of both drugs to prevent excessive weight loss.Justin Lee, a researcher specialising in metabolic biology, who led the study, says the drugs work so well together because they act on ‘complementary targets’.Tirzepatide worked particularly well because it stimulates two gut hormones, GLP-1 and GIP, which help suppress appetite, while semaglutide acts on GLP-1 alone.Together, the drugs reduce the amount of food being eaten while increasing the energy the body burns, producing ‘a strong, overall negative energy balance that translates to weight loss and metabolic improvement’, says Justin Lee. ‘If we can use smaller doses of semaglutide or tirzepatide, we could decrease gut side-effects.’Nausea, vomiting, diarrhoea and constipation are common side-effects of drugs such as Wegovy.Although the mice did not show any bad side-effects, TOFA has yet to be tested in humans so its full safety profile is unknown.Its potential benefits may also extend beyond weight loss.Taken alone, it improved blood-sugar control in mice – potentially reducing the risk of type 2 diabetes – and lowered triglycerides, a type of fat in the blood linked to heart disease. It also reduced harmful fat accumulation in the liver.Naveed Sattar, a professor of metabolic medicine at the University of Glasgow, told Good Health: ‘New drugs that help people lose weight by increasing calorie burning represent an important advance. But rigorous safety assessments will be essential.’Because TOFA increases energy expenditure, researchers will need to establish that it does not cause excessive heat production or put strain on the heart. Also, other drugs that target the same pathway have in the past been found to increase triglyceride levels in humans – potentially raising the risk of heart disease and pancreatitis – while others affected platelet levels, which could up the risk of bleeding.Alex Miras, a clinical professor of medicine at Ulster University and an obesity specialist, says: ‘Even though this is just an animal study, these are exciting findings.‘At the moment these types of combinations are a real unmet need, as people who do not respond enough to GLP-1-based drugs have no other drug options.’