An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss

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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-09-25
DOI
https://doi.org/10.1073/pnas.2618845123
Primary Topic
Adipose Tissue and Metabolism
Type
article
Field-Weighted Citation Impact
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article

An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss

Alexander R. Keeble, Clara Bien Peek, Biliana Marcheva, Nicholas J. Conley et al.
Proceedings of the National Academy of Sciences
Adipose Tissue and Metabolism
article

An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss

Alexander R. Keeble, Clara Bien Peek, Biliana Marcheva, Nicholas J. Conley, Mark Perelis, Joseph T. Bass, Lisa R. Beutler, Yasuhiro Omura, Yumiko Kobayashi, Hannah Guak, Nathan J. Waldeck, Jesse P. Rose, Andrew B. Cohen, Kathryn Moynihan Ramsey, Chiaki Omura, Marisa J. Stachowski, Anneke K. Thorne, Rana K. Gupta, Elizabeth M. McNally, Grant D. Barish, Weimin Song, Pei Zhu, Britta Kuusik, Chelsea Hepler, Ella Simon, Ling Wa Chong, Michael Wellems, Joseph V. Mastroni
article en

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.

Proceedings of the National Academy of SciencesVol. 123(40)
Duke University (US), University of Michigan (US), Ionis Pharmaceuticals (United States) (US), Duke Medical Center (US), ProNAi Therapeutics (United States) (US)
Affordable and clean energy
Openalex Percentile: Top 11%
Adipose Tissue and Metabolism
DOIOpen Access PDFOpenAlex
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