ArticleProceedings of the National Academy of Sciences of the United States of America2026
An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss.
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Article in Proceedings of the National Academy of Sciences of the United States of America, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1citing papers in PubMed
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1 citing paper in PubMed.
- An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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Authors and funding
28 authors.
Anneke K ThorneDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0001-5069-6497
Nathan J WaldeckDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Jesse P RoseDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Marisa J StachowskiCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0003-3291-6112
Hannah GuakDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Alexander R KeebleCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Britta KuusikDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Ella SimonDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0009-0003-3154-2232
Biliana MarchevaDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Joseph V MastroniDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0009-0004-5171-5417
Pei ZhuDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-0321-9636
Ling Wa ChongIonis Pharmaceuticals, Carlsbad, CA 92010.
Yumiko KobayashiDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Nicholas J ConleyDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0001-7160-9719
Andrew B CohenDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0009-0009-7207-8337
Yasuhiro OmuraDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Chiaki OmuraDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Weimin SongDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Michael WellemsPhenome Technologies Inc., Lincolnshire, IL 60091.
Kathryn M RamseyDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Grant D BarishDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0001-8753-0546
Lisa R BeutlerDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-9489-8098
Rana K GuptaDivision of Endocrinology, Department of Medicine, Duke Molecular Physiology Institute, Duke University, Durham, NC 27701.
Clara B PeekDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0003-0873-0879
Elizabeth M McNallyCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-1221-719X
Chelsea HeplerDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.
Mark PerelisIonis Pharmaceuticals, Carlsbad, CA 92010.ORCID 0000-0001-5435-2552
Joseph BassDepartment of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.ORCID 0000-0002-1602-8601
Funding
Tumor Environment and Metastasis (TEAM) Research ProgramP30CA060553 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Devalingam Mahalingam · 1993 to 2026
$153.9MSLOW WAVE SLEEP AND TYPE 2 DIABETES RISK IN AGINGP01AG011412 · NIA · UNIVERSITY OF CHICAGO · PI ZEE, PHYLLIS C. · 1994 to 2021
$31.5MPilot and Feasibility ProgramP30DK020595 · NIDDK · UNIVERSITY OF CHICAGO · PI RONALD N COHEN · 2013 to 2026
$20.9MTRAINING GRANT IN SLEEP RESEARCHT32HL007909 · NHLBI · NORTHWESTERN UNIVERSITY · PI FRED W TUREK, Phyllis C. Zee · 1998 to 2026
$9.2MMyoferlin in Muscle Membrane Fusion and RepairR01NS047726 · NINDS · UNIVERSITY OF CHICAGO · PI ALEXIS R. DEMONBREUN, Elizabeth M McNally · 2003 to 2026
$7.2MIntegration of Feeding Time and Glucose Metabolism by the Circadian Gene NetworkR01DK090625 · NIDDK · NORTHWESTERN UNIVERSITY AT CHICAGO · PI BASS, JOSEPH, LERNER, TALIA NEWCOMBE · 2011 to 2025
$6.9MTRAINING IN METABOLISM, DIABETES AND ENDOCRINOLOGYT32DK007169 · NIDDK · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Joseph Bass · 1988 to 2026
$6.6MTraining Core - Judge_Crosbie(UCLA)P50HD119693 · NICHD · UNIVERSITY OF FLORIDA · PI H Lee Sweeney · 2025 to 2026
$3.9MNuclear Repressors in Genomic Control of Healthful ObesityR01DK108987 · NIDDK · NORTHWESTERN UNIVERSITY AT CHICAGO · PI BARISH, GRANT D · 2016 to 2024
$3.4MExtracellular matrix regulation of cellular crosstalk in cardiac fibrosisR01HL167813 · NHLBI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI ALEXIS R. DEMONBREUN, Elizabeth M McNally · 2023 to 2026
$2.8MClock Control of Muscle Glucose Metabolism and HIF ActivityR01DK123358 · NIDDK · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Clara Bien Peek · 2020 to 2026
$2.4MCross-regulation of Immunometabolism and Circadian Pathways in Obesity PathophysiologyR01DK127800 · NIDDK · NORTHWESTERN UNIVERSITY AT CHICAGO · PI BASS, JOSEPH · 2021 to 2025
$2.3MAmerican Diabetes Association (ADA) 1-24-INI-01American Diabetes Association (ADA) 4-24-PDF-81BLRD VA I01 BX004898HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) P50HD119693HHS | NIH | National Center for Advancing Translational Sciences (NCATS) R21TR005472HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) F32HL177905HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL167813HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) T32HL007909HHS | NIH | National Human Genome Research Institute (NHGRI) U01HG013745HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) F31DK141117HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) F32DK122675HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) F32DK147949HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) P30DK020595HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK090625HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK108987HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK113011HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK123358HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK127800HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK128477HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK132647HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK142852HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK143978HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) T32DK007169HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS047726HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) UH3NS127383HHS | NIH | National Institute on Aging (NIA) P01AG011412HHS | NIH | National Institute on Aging (NIA) R01AG065988HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM) F31DK130589NCATS NIH HHS R21 TR005472NCI NIH HHS P30 CA060553NHGRI NIH HHS U01 HG013745NHLBI NIH HHS F32 HL177905NHLBI NIH HHS R01 HL167813NHLBI NIH HHS T32 HL007909NIA NIH HHS P01 AG011412NIA NIH HHS R01 AG065988NICHD NIH HHS P50 HD119693NIDDK NIH HHS F31 DK130589NIDDK NIH HHS F31 DK141117NIDDK NIH HHS F32 DK122675NIDDK NIH HHS F32 DK147949NIDDK NIH HHS P30 DK020595NIDDK NIH HHS R01 DK090625NIDDK NIH HHS R01 DK108987NIDDK NIH HHS R01 DK113011NIDDK NIH HHS R01 DK123358NIDDK NIH HHS R01 DK127800NIDDK NIH HHS R01 DK128477NIDDK NIH HHS R01 DK132647NIDDK NIH HHS R01 DK142852NIDDK NIH HHS R01 DK143978NIDDK NIH HHS T32 DK007169NINDS NIH HHS R01 NS047726NINDS NIH HHS UH3 NS127383U.S. Department of Veterans Affairs (VA) I01BX004898
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
Indexed as
Glucagon-Like Peptide 1ObesityOligonucleotides, AntisenseRNAThermogenesisWeight LossAnimalsDNA-Binding ProteinsEnergy MetabolismMaleMiceMice, Inbred C57BLSemaglutideTranscription FactorsDNA-Binding ProteinsGlucagon-Like Peptide 1Oligonucleotides, AntisenseRNASemaglutideTranscription Factorsadipose thermogenesisantisense oligonucleotideGLP-1 receptor agonistobesityZFP423
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