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An RNA Thermogenic Therapy to Preserve Lean Mass and Enhance Metabolic Health During GLP-1 Weight Loss [snRNA-Seq]

ABSTRACT: Current obesity therapies reduce weight but often fail to preserve lean mass or sustain metabolic benefit. Glucagon-like peptide-1 receptor agonists (GLP-1RA) improve obesity-associated metabolic disease, but weight loss is often accompanied by reduced energy expenditure, loss of lean mass, and rapid fat-predominant regain after treatment discontinuation. We hypothesized that pharmacologic activation of adipose thermogenesis could specifically target fat loss, complement appetite suppression by increasing energy expenditure, and improve the metabolic quality of weight loss. Guided by our finding that diet-induced thermogenesis is mediated by a zinc finger protein 423 (ZFP423)-controlled pathway, we developed adipose-directed antisense oligonucleotides (ASOs) targeting ZFP423, a transcriptional repressor of brown and beige adipocyte identity. In lean and diet-induced obese mice, weekly Zfp423 ASO treatment induced white adipose beiging, increased body temperature and oxygen consumption, and improved glucose homeostasis, insulin sensitivity, lipid metabolism, mitochondrial respiration and hepatic steatosis. When combined with the GLP1-RA semaglutide, Zfp423 ASO produced greater weight and fat loss than either monotherapy while preserving lean mass and improving metabolic outcomes. These findings identify Zfp423 as an RNA therapeutic target and support adipose thermogenesis as a complementary strategy for metabolically healthier obesity treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE346803 | GEO | 2026/09/20

REPOSITORIES: GEO

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Project description:Background and aims: The glucagon-like peptide-1 receptor agonist semaglutide is an antidiabetic medication that has recently been approved for treatment of obesity as well. While its efficacy on weight management is well established, associated concomitant loss of muscle mass can be a potential drawback. In this study, we investigated whether combining semaglutide with exercise could enhance its metabolic effects while mitigating muscle loss. Method: Ldlr−/−.Leiden mice were fed a high fat diet (HFD) for 20 weeks to induce obesity, insulin resistance, metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. Mice were subsequently left untreated (control) or treated for 14 weeks with semaglutide, exercise (running wheel) or the combination thereof. Histological examination and comprehensive transcriptome analyses were conducted on white adipose tissue, muscle, liver and heart to explore underlying mechanisms. Results: Semaglutide significantly reduced fat mass (-31%) but also lean mass (-11%). Combining semaglutide with exercise further reduced fat mass (-45%) and lean mass as well but to a lesser extent (-8%). Semaglutide alone or combined with exercise significantly improved insulin sensitivity, plasma cholesterol and triglycerides. The combination of semaglutide with exercise improved , adipose tissue inflammation, liver steatosis, liver inflammation and atherosclerotic lesion area. With regard to muscle parameters, combination treatment significantly improved grip strength and diameter of gastrocnemius myocytes, while these parameters were not affected by either treatment alone. Pathway analysis revealed complementary effects of semaglutide and exercise on metabolic, inflammatory and a variety of other pathways, thereby substantiating the added value of combining semaglutide with exercise. Conclusion: Semaglutide has broad beneficial effects on circulating risk factors of metabolic syndrome, liver, vascular and adipose parameters but decreases lean mass and muscle strength. By combining semaglutide intervention with exercise, these parameters are further improved with a partial preservation of lean mass and muscle function.

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An RNA Thermogenic Therapy to Preserve Lean Mass and Enhance Metabolic Health During GLP-1 Weight Loss [snRNA-Seq]

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