PNAS Study Finds Experimental RNA Therapy Preserved Lean Mass When Combined With Semaglutide in Mice

The Proceedings of the National Academy of Sciences (PNAS) published a study online September 25, 2026 describing an experimental RNA-based therapy that preserved lean muscle mass when combined with the GLP-1 receptor agonist semaglutide in mice, addressing a widely discussed drawback of GLP-1 obesity treatments: the loss of muscle along with fat during weight loss, and the tendency for patients who stop treatment to regain weight primarily as fat.

The study, led by senior author Dr. Joseph Bass, director of the Center for Diabetes and Metabolism at Northwestern University Feinberg School of Medicine, with first author Anneke Thorne, developed an antisense oligonucleotide (ASO), a short strand of RNA designed to silence a specific gene, that targets ZFP423. According to the paper's abstract and the Northwestern press release describing it, ZFP423 acts as a transcriptional repressor that normally suppresses the identity of brown and beige adipocytes, the fat cells that burn energy to produce heat rather than storing it. By silencing ZFP423, the therapy reprogrammed white fat, which stores energy, toward a beige-fat, calorie-burning state, a process the researchers call adipose beiging.

The researchers first tested the ASO alone in lean mice and in diet-induced obese mice. According to the Northwestern release, weekly treatment "tremendously" improved glucose tolerance while reducing body fat, and Bass said he found it "amazing" that the therapy reduced fat tissue without causing muscle loss. The team then tested whether combining the ASO with semaglutide, a once-weekly GLP-1 receptor agonist, could enhance the drug's effects. Throughout the experiments, the researchers tracked body weight, fat mass, lean mass, energy expenditure, blood sugar, and other metabolic measures including insulin sensitivity.

In the combination experiment, mice receiving both the ASO and semaglutide lost more weight and fat than mice receiving semaglutide alone, while losing significantly less lean mass. According to the Northwestern release, mice on the combination treatment lost about 5.5% of their lean mass, compared with about 10% for mice on semaglutide alone. The combination group also ended treatment with less body fat, about 4 grams, compared with nearly 8 grams for the semaglutide-only group. The combined treatment also improved glucose tolerance and other measures of metabolic health relative to semaglutide alone, the release states.

"We have identified, for the first time, an RNA therapy that promotes thermogenesis and, when combined with the GLP-1 drug semaglutide, helps preserve lean muscle mass," Bass said in the Northwestern release. The study traces its origins to earlier research by Chelsea Hepler, now at the University of Michigan, on the link between the body's internal clock and fat beiging, which built on prior work by Rana Gupta at Duke University identifying ZFP423 as a brake on that process. Bass's team developed the RNA therapy targeting ZFP423 with Ionis Pharmaceuticals, a company that specializes in RNA-based therapeutics; two Ionis employees, Michael Perelis and Lynnie W. Chong, are listed as co-authors, and the paper's competing-interests statement discloses that Ionis holds patents on the ASO chemistry and design used in the study.

The study was conducted entirely in mice, and its authors have not published human data. Northwestern says Bass's team is now testing similar RNA therapies in human cells, an earlier stage than human clinical trials. Northwestern has filed a provisional patent application related to the ZFP423-targeting therapy, naming Bass and Thorne as inventors, and the paper's competing-interests statement discloses that filing along with Elizabeth McNally's board and advisory roles at Novartis and PepGen. The study was supported in part by the National Institutes of Health. Semaglutide, marketed as Ozempic and Rybelsus for type 2 diabetes and Wegovy for chronic weight management, remains approved by the FDA, the European Medicines Agency, and Australia's Therapeutic Goods Administration for those indications; this mouse study does not change that regulatory status, does not establish that the ASO-semaglutide combination is safe or effective in humans, and is not treatment or dosing guidance. Any decision about semaglutide use should be made with a qualified clinician based on its approved indications.