An experimental RNA therapy that turns energy-storing white fat into calorie-burning beige fat could potentially address one of the drawbacks of GLP-1 obesity drugs: the loss of lean mass along with body fat.
In a mouse study, Northwestern University researchers found that suppressing a gene that normally restrains fat-burning thermogenesis increased energy expenditure and improved several measures of metabolic health. When the RNA treatment was combined with semaglutide, mice lost more weight and fat than with either treatment alone while retaining substantially more lean mass.
The findings, published in Proceedings of the National Academy of Sciences, suggest that stimulating energy expenditure could complement the appetite-suppressing effects of GLP-1 receptor agonists and potentially improve the metabolic quality of weight loss.
GLP-1 drugs such as semaglutide can produce substantial weight loss and improve obesity-related metabolic disease. But weight loss can include reductions in lean mass, and declining body weight triggers biological adaptations—including reduced energy expenditure—that favor weight regain. After treatment ends, regained weight may also disproportionately consist of fat rather than lean tissue.
The Northwestern team targeted zinc finger protein 423 (ZFP423), a transcriptional regulator that suppresses the development of thermogenic brown and beige fat cells. Earlier research had shown that reducing ZFP423 activity in white adipose tissue could restore thermogenic capacity and protect mice against excessive weight gain and metabolic dysfunction.
For the new study, researchers developed adipose-directed antisense oligonucleotides (ASOs) that suppress ZFP423. ASOs are short strands of synthetic nucleic acid designed to bind specific RNA molecules and alter expression of a targeted gene.
Weekly Zfp423 ASO treatment promoted “beiging” of white adipose tissue and increased body temperature, oxygen consumption, and mitochondrial activity in both lean and diet-induced obese mice. The treatment also improved glucose regulation, insulin sensitivity, and lipid metabolism and reduced accumulation of fat in the liver.
Importantly, the animals lost fat without a corresponding reduction in lean mass. The researchers also reported that Zfp423 ASO-treated mice maintained or improved muscle strength.
The effects became particularly notable when the RNA therapy was paired with semaglutide. Combination treatment produced greater weight and fat loss than either therapy alone. Mice receiving the combination lost about 5.5% of their lean mass, compared with approximately 10% among mice receiving semaglutide alone. At the end of treatment, mice receiving both therapies had approximately four grams of body fat, versus nearly eight grams with semaglutide alone.
The combination also improved glucose tolerance and reduced liver triglycerides, suggesting that activating thermogenesis may provide metabolic benefits beyond additional weight loss.
Important questions remain before the approach can move toward clinical use. The study was conducted in mice, and the ASOs were designed to target mouse Zfp423 rather than its human counterpart, ZNF423. The researchers have not yet demonstrated that suppressing ZNF423 can produce the same thermogenic effects in human fat cells.
The team is now investigating related RNA approaches in human cells. If the mechanism translates to humans, targeting adipose thermogenesis could eventually provide a complementary strategy to GLP-1 therapy—shifting obesity treatment toward maximizing fat loss while better preserving metabolically important lean tissue.
