Evidence map›Paper›PMID 41654015›Full record

ArticleMolecular metabolism2026

Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues.

Jonathan D Douros, Megan Capozzi, Aaron Novikoff, Jacek Mokrosinski, Barent DuBois, Joseph Stock, Rebecca Rohlfs, Mikayla Anderson, Dominika J Jedrzejcyk, Svend Poulsen and 15 more

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Article in Molecular metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors.

Jonathan D DourosNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
Megan CapozziDuke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Aaron NovikoffInstitute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
Jacek MokrosinskiNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
Barent DuBoisNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
Joseph StockNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
Rebecca RohlfsNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
Mikayla AndersonNovo Nordisk Research Center Seattle, Seattle, WA, USA.
Dominika J JedrzejcykNovo Nordisk A/S, Måløv, Denmark.
Svend PoulsenNovo Nordisk A/S, Måløv, Denmark.
Erik Oude BlenkeNovo Nordisk A/S, Måløv, Denmark.
Tomas DagoNovo Nordisk A/S, Måløv, Denmark.
Kasper HuusNovo Nordisk A/S, Måløv, Denmark.
Peder L NørbyNovo Nordisk A/S, Måløv, Denmark.
Sune KobberupNovo Nordisk A/S, Måløv, Denmark.
Marita RivirDepartment of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Joyce SorrellDepartment of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Stephanie A MoweryNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
Daniel J DruckerLunenfeld Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON, Canada.
David A D'AlessioDuke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Jonathan E CampbellDuke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Timo D MüllerInstitute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University (LMU) Munich, Germany.
Diego Perez-TilveDepartment of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Brian FinanNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
Patrick J KnerrNovo Nordisk Research Center Indianapolis, Indianapolis, IN, USA. Electronic address: pknerr@indianabiosciences.org.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

objectivesUnimolecular triagonists drive substantial weight loss in patients with obesity by engaging the glucagon-like peptide 1 receptor (GLP-1R) and glucose dependent insulinotropic polypeptide receptor (GIPR) to reduce food intake (FI) and the hepatic glucagon receptor (GcgR) to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects, including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R mono-agonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes.

methodsWe used an adeno-associated virus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure.

resultsAgonism of the ectopic GLP-1R with either semaglutide, a cAMP biased GLP-1R analogue (NNC5840), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to peptide agonist treatment alone.

conclusionsThis represents a novel mechanism for achieving poly-pharmacology to treat obesity.

Indexed as

Glucagon-Like Peptide 1Glucagon-Like Peptide-1 Receptor AgonistsWeight LossAnimalsEnergy MetabolismGlucagon-Like Peptide-1 ReceptorGlucagon-Like PeptidesHepatocytesHumansLiverMaleMiceMice, Inbred C57BLObesityReceptors, GlucagonSemaglutideGlp1r protein, mouseGlucagon-Like Peptide 1Glucagon-Like Peptide-1 ReceptorGlucagon-Like Peptide-1 Receptor AgonistsGlucagon-Like PeptidesReceptors, GlucagonSemaglutideEnergy expenditureGLP-1GlucagonObesityPharmacology

Identifiers

PMID41654015
PMCPMC12926979

What Socratic holds

Texttitle and abstract
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.