Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40):
e2618845123
Anneke K Thorne,
Nathan J Waldeck,
Jesse P Rose,
Marisa J Stachowski,
Hannah Guak,
Alexander R Keeble,
Britta Kuusik,
Ella Simon,
Biliana Marcheva,
Joseph V Mastroni,
Pei Zhu,
Ling Wa Chong,
Yumiko Kobayashi,
Nicholas J Conley,
Andrew B Cohen,
Yasuhiro Omura,
Chiaki Omura,
Weimin Song,
Michael Wellems,
Kathryn M Ramsey,
Grant D Barish,
Lisa R Beutler,
Rana K Gupta,
Clara B Peek,
Elizabeth M McNally,
Chelsea Hepler,
Mark Perelis,
Joseph Bass.
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.
Keywords: GLP-1 receptor agonist; ZFP423; adipose thermogenesis; antisense oligonucleotide; obesity