RNA therapy could help preserve muscle mass during treatment with semaglutide

An experimental RNA therapy developed at Northwestern University has enhanced weight and fat loss in mice treated with semaglutide while substantially reducing the loss of lean tissue

An experimental RNA therapy could help to address one of the principal limitations of glucagon-like peptide-1 (GLP-1) medicines how its use leads to the loss of muscle mass alongside fat during treatment for obesity.

The mouse model research at Northwestern University, Evanston, Illinois, USA, prompted the body to expend more energy as heat and enhanced the effects of semaglutide (Wegovy, Ozempic) a GLP-1 medicine. Mice that received both treatments lost more weight and body fat than those that received semaglutide alone but – crucially – retained a greater proportion of their lean mass.

The researchers said that the study provided the first evidence that an RNA therapy could activate thermogenesis, the biological process through which the body burns calories to generate heat. The experimental treatment achieved this effect by reprogramming white fat, which primarily stores energy, so that it acquired characteristics of beige fat, which can consume energy and produce heat.

“For the first time we have identified an RNA therapy that promotes thermogenesis and – when combined with … semaglutide – helps preserve lean muscle mass,” said the study’s senior author, Dr Joseph Bass, director of the Center for Diabetes and Metabolism at Northwestern University Feinberg School of Medicine.

Bass and his colleagues first assessed the RNA therapy on its own in mice fed either a standard diet or a high-fat diet. After the initial experiments produced encouraging results, the researchers combined the therapy with semaglutide to determine whether it could improve the medicine’s metabolic effects.

Throughout the experiments, the team measured body weight, body fat, lean mass, energy expenditure and blood glucose. The researchers also assessed several other indicators of metabolic health, including insulin sensitivity and glucose tolerance, which reflect how effectively the body responds to insulin and regulates sugar in the blood.

The therapy uses a short strand of RNA to suppress zinc finger protein 423 (ZFP423) a gene that restricts the ability of white fat cells to acquire the energy-consuming properties of beige fat. By silencing the gene, the treatment effectively released this biological ‘brake’ and increased the capacity of fat tissue to expend energy.

The therapy produced notable metabolic effects even in mice fed a standard diet. It substantially improved glucose tolerance and reduced body fat without a corresponding loss of muscle.

“It tremendously improved glucose tolerance and it was amazing to see a reduction in fat tissue without any loss of muscle,” Bass said of the initial findings.

The strongest results emerged from the final experiment, in which the researchers combined the RNA therapy with semaglutide. Mice that received both treatments lost only 5.5 per cent of their lean mass, compared with approximately 10 per cent among mice treated with semaglutide alone.

The combined treatment also produced a greater reduction in body fat. At the end of the treatment period, mice in the combination group had approximately 4 grams of body fat, compared with nearly 8 grams among those that received semaglutide alone. The dual therapy also improved glucose tolerance and other measures of metabolic health.

GLP-1 medicines have transformed the treatment of obesity but weight loss associated with these drugs can include a clinically significant reduction in lean tissue, which encompasses skeletal muscle. Muscle is critical for strength, physical function and metabolic health. Patients can also regain weight after they stop treatment and much of this regained weight can take the form of fat rather than restored muscle.

A treatment that promotes fat loss while protecting lean tissue could therefore improve the quality – rather than merely the quantity – of weight loss. However further research will be necessary to establish whether the approach is safe and effective for use in human.

The work arose from an earlier question about why the same number of calories could produce different amounts of weight gain when consumed at different times of day. Dr. Chelsea Hepler – now at the University of Michigan, Ann Arbor – led research into that question and identified a connection between the body’s internal clock and its capacity to convert white fat into beige fat.

That research built upon work by Dr. Rana Gupta, a professor in the department of medicine and division of endocrinology and metabolism at Duke University, Durham, North Carolina, who had identified the role of ZFP423 as a brake on the ‘beiging’ of fat. Bass and his colleagues subsequently sought a drug candidate that could release this brake. They developed the experimental treatment with support from Ionis Pharmaceuticals, a company that specialises in RNA-based medicines.

The Northwestern researchers have now begun to assess similar RNA therapies in human cells. These laboratory studies represent an early step towards possible clinical development and the treatment will require extensive safety and efficacy evaluation before it can be considered for use in patients.

Northwestern University has filed a provisional patent application related to the experimental RNA therapy. Bass and the study’s first author, Dr. Anneke Thorne, have been named as inventors.

For further reading please visit: 10.1073/pnas.2618845123