ArticleNature medicine2015
A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 278 papers.
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Who cites it
278 citing papers in PubMed, 614 citations in OpenAlex.
- Appetite, eating attitudes, and eating behaviours during treatment with retatrutide in adults with type 2 diabetes: Results of a phase 2 study.Diabetes, obesity & metabolism · 2025Trial
- A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.Nature metabolism · 2024Trial
- Acute Effects of Glucagon on Reproductive Hormone Secretion in Healthy Men.The Journal of clinical endocrinology and metabolism · 2020Trial
- Detection and Excretion Profile of Retatrutide in Human Plasma and Urine by LC-HRMS: Implications for Antidoping Analysis.Rapid communications in mass spectrometry : RCM · 2026Article
- The PTPN1/N2 Peptide Inhibitor Achieves Potent, Long-Acting Glycemic Control and Weight-Loss Dual Efficacy in Mice.ACS omega · 2026Article
- Peptide Marriages: Modular Assembly of Multi-Agonist Therapeutics.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Future GLP-1 receptor co-agonists and their cardiac effects.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.Nature metabolism · 2026Article
- The evolving landscape of obesity pharmacotherapy.Nature reviews. Drug discovery · 2026Review
- Design of a metabolically-stable peptide therapeutic with triple-hormone-receptor agonist activity.Journal of computer-aided molecular design · 2026Article
- Discovery of Biased Dual-Agonists of Glucagon-Like Peptide 1 and Glucagon Receptors through Mutation of a Conserved Aspartate.ACS medicinal chemistry letters · 2026Article
- GIPR:GCGR co-agonism restores normal weight in obese rodents.Molecular metabolism · 2026Article
- Hypothalamic regulation of energy homeostasis: Quo vadis.Reviews in endocrine & metabolic disorders · 2026Review
- Identification of a novel oral potential multiple agonist for obesity treatment: multi-target in silico study.Journal of computer-aided molecular design · 2026Article
- The Emerging Role of Glucagon-like Peptide 1 (GLP-1)-Based Medications in the Treatment of Heart Failure, with a Focus on Heart Failure with Preserved or Mildly Reduced Ejection Fraction.Medicina (Kaunas, Lithuania) · 2026Review
- Discovery of AMG 133, a Glucose-Dependent Insulinotropic Polypeptide Receptor Antagonist and Glucagon-Like Peptide 1 Receptor Agonist Antibody-Drug Conjugate for the Treatment of Obesity.Journal of medicinal chemistry · 2026Article
- The expanding landscape of the glucagon signaling network: mechanisms and outcomes.Endocrinology · 2026Review
- Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues.Molecular metabolism · 2026Article
- GCGR agonism requires GABAergic signaling in the medial basal hypothalamus to promote weight loss in obese mice.Molecular metabolism · 2026Article
- Prolonged Somatostatin Receptor 2 Antagonism Enhances Glucagon Response to Hypoglycemia in Male Diabetic Rats.Endocrinology · 2026Article
218 more citing papers are in PubMed but not listed here.
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Authors and funding
29 authors at 7 institutions in 4 countries.
Funding
Abstract
We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.
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Registered trials
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 OpenQuestion graph.