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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

In: Nature Medicine, Vol. 21, No. 1, 01.2015, p. 27-36.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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

APA

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

Vancouver

Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nature Medicine. 2015 Jan;21(1):27-36. https://doi.org/10.1038/nm.3761

Author

Finan, Brian ; Yang, Bin ; Ottaway, Nickki ; Smiley, David L ; Ma, Tao ; Clemmensen, Christoffer ; Chabenne, Joe ; Zhang, Lianshan ; Habegger, Kirk M ; Fischer, Katrin ; Campbell, Jonathan E ; Sandoval, Darleen ; Seeley, Randy J ; Bleicher, Konrad ; Uhles, Sabine ; Riboulet, William ; Funk, Jürgen ; Hertel, Cornelia ; Belli, Sara ; Sebokova, Elena ; Conde-Knape, Karin ; Konkar, Anish ; Drucker, Daniel J ; Gelfanov, Vasily ; Pfluger, Paul T ; Müller, Timo D ; Perez-Tilve, Diego ; DiMarchi, Richard D ; Tschöp, Matthias H. / A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. In: Nature Medicine. 2015 ; Vol. 21, No. 1. pp. 27-36.

Bibtex

@article{b384be14d3fc406fab9ac1164c19c2ea,
title = "A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents",
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.",
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",
author = "Brian Finan and Bin Yang and Nickki Ottaway and Smiley, {David L} and Tao Ma and Christoffer Clemmensen and Joe Chabenne and Lianshan Zhang and Habegger, {Kirk M} and Katrin Fischer and Campbell, {Jonathan E} and Darleen Sandoval and Seeley, {Randy J} and Konrad Bleicher and Sabine Uhles and William Riboulet and J{\"u}rgen Funk and Cornelia Hertel and Sara Belli and Elena Sebokova and Karin Conde-Knape and Anish Konkar and Drucker, {Daniel J} and Vasily Gelfanov and Pfluger, {Paul T} and M{\"u}ller, {Timo D} and Diego Perez-Tilve and DiMarchi, {Richard D} and Tsch{\"o}p, {Matthias H}",
year = "2015",
month = jan,
doi = "10.1038/nm.3761",
language = "English",
volume = "21",
pages = "27--36",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

AU - Finan, Brian

AU - Yang, Bin

AU - Ottaway, Nickki

AU - Smiley, David L

AU - Ma, Tao

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

AU - Perez-Tilve, Diego

AU - DiMarchi, Richard D

AU - Tschöp, Matthias H

PY - 2015/1

Y1 - 2015/1

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.

KW - Animals

KW - Blood Glucose

KW - Body Weight

KW - Diabetes Complications

KW - Diabetes Mellitus, Type 2

KW - Glucagon-Like Peptide 1

KW - HEK293 Cells

KW - Humans

KW - Insulin

KW - Mice

KW - Obesity

KW - Peptides

KW - Rats

KW - Receptors, Gastrointestinal Hormone

KW - Receptors, Glucagon

KW - Rodentia

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nm.3761

DO - 10.1038/nm.3761

M3 - Journal article

C2 - 25485909

VL - 21

SP - 27

EP - 36

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 1

ER -

ID: 186640448