A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Brian Finan; Bin Yang; Nickki Ottaway; David L Smiley; Tao Ma; Christoffer Clemmensen; Joe Chabenne; Lianshan Zhang; Kirk M Habegger; Katrin Fischer; Jonathan E Campbell; Darleen Sandoval; Randy J Seeley; Konrad Bleicher; Sabine Uhles; William Riboulet; Jürgen Funk; Cornelia Hertel; Sara Belli; Elena Sebokova; Karin Conde-Knape; Anish Konkar; Daniel J Drucker; Vasily Gelfanov; Paul T Pfluger; Timo D Müller; Diego Perez-Tilve; Richard D DiMarchi; Matthias H Tschöp

doi:10.1038/nm.3761

A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Brian Finan, Bin Yang, Nickki Ottaway, David L Smiley, Tao Ma, Christoffer Clemmensen, Joe Chabenne, Lianshan Zhang, Kirk M Habegger, Katrin Fischer, Jonathan E Campbell, Darleen Sandoval, Randy J Seeley, Konrad Bleicher, Sabine Uhles, William Riboulet, Jürgen Funk, Cornelia Hertel, Sara Belli, Elena SebokovaKarin Conde-Knape, Anish Konkar, Daniel J Drucker, Vasily Gelfanov, Paul T Pfluger, Timo D Müller, Diego Perez-Tilve, Richard D DiMarchi, Matthias H Tschöp

313 Citations (Scopus)

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.

Original language	English
Journal	Nature Medicine
Volume	21
Issue number	1
Pages (from-to)	27-36
Number of pages	10
ISSN	1078-8956
DOIs	https://doi.org/10.1038/nm.3761
Publication status	Published - 1 Jan 2015

Keywords

Animals
Blood Glucose
Body Weight
Diabetes Complications
Diabetes Mellitus, Type 2
Glucagon-Like Peptide 1
HEK293 Cells
Humans
Insulin
Mice
Obesity
Peptides
Rats
Receptors, Gastrointestinal Hormone
Receptors, Glucagon
Rodentia
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.3761

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Finan, B., Yang, B., Ottaway, N., Smiley, D. L., Ma, T., Clemmensen, C., Chabenne, J., Zhang, L., Habegger, K. M., Fischer, K., Campbell, J. E., Sandoval, D., Seeley, R. J., Bleicher, K., Uhles, S., Riboulet, W., Funk, J., Hertel, C., Belli, S., ... Tschöp, M. H. (2015). A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nature Medicine, 21(1), 27-36. https://doi.org/10.1038/nm.3761

Finan, B, Yang, B, Ottaway, N, Smiley, DL, Ma, T, Clemmensen, C, Chabenne, J, Zhang, L, Habegger, KM, Fischer, K, Campbell, JE, Sandoval, D, Seeley, RJ, Bleicher, K, Uhles, S, Riboulet, W, Funk, J, Hertel, C, Belli, S, Sebokova, E, Conde-Knape, K, Konkar, A, Drucker, DJ, Gelfanov, V, Pfluger, PT, Müller, TD, Perez-Tilve, D, DiMarchi, RD & Tschöp, MH 2015, 'A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents', Nature Medicine, vol. 21, no. 1, pp. 27-36. https://doi.org/10.1038/nm.3761

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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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AU - Finan, Brian

AU - Yang, Bin

AU - Ottaway, Nickki

AU - Smiley, David L

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AU - Clemmensen, Christoffer

AU - Chabenne, Joe

AU - Zhang, Lianshan

AU - Habegger, Kirk M

AU - Fischer, Katrin

AU - Campbell, Jonathan E

AU - Sandoval, Darleen

AU - Seeley, Randy J

AU - Bleicher, Konrad

AU - Uhles, Sabine

AU - Riboulet, William

AU - Funk, Jürgen

AU - Hertel, Cornelia

AU - Belli, Sara

AU - Sebokova, Elena

AU - Conde-Knape, Karin

AU - Konkar, Anish

AU - Drucker, Daniel J

AU - Gelfanov, Vasily

AU - Pfluger, Paul T

AU - Müller, Timo D

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AU - Tschöp, Matthias H

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N2 - 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.

AB - 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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SP - 27

EP - 36

JO - Nature Medicine

JF - Nature Medicine

IS - 1

ER -

A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Abstract

Keywords

UN SDGs

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