title: A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.
abstract: We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.
authors: Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
authors: Jonathan W
authors: JW
authors: Day
authors: Nickki
authors: N
authors: Ottaway
authors: James T
authors: JT
authors: Patterson
authors: Vasily
authors: V
authors: Gelfanov
authors: David
authors: D
authors: Smiley
authors: Jas
authors: J
authors: Gidda
authors: Hannes
authors: H
authors: Findeisen
authors: Dennis
authors: D
authors: Bruemmer
authors: Daniel J
authors: DJ
authors: Drucker
authors: Nilika
authors: N
authors: Chaudhary
authors: Jenna
authors: J
authors: Holland
authors: Jazzminn
authors: J
authors: Hembree
authors: William
authors: W
authors: Abplanalp
authors: Erin
authors: E
authors: Grant
authors: Jennifer
authors: J
authors: Ruehl
authors: Hilary
authors: H
authors: Wilson
authors: Henriette
authors: H
authors: Kirchner
authors: Sarah Haas
authors: SH
authors: Lockie
authors: Susanna
authors: S
authors: Hofmann
authors: Stephen C
authors: SC
authors: Woods
authors: Ruben
authors: R
authors: Nogueiras
authors: Paul T
authors: PT
authors: Pfluger
authors: Diego
authors: D
authors: Perez-Tilve
authors: Richard
authors: R
authors: DiMarchi
authors: Matthias H
authors: MH
authors: Tschöp
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D005951:Glucose Tolerance Test; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009765:Obesity / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011487:Protein Conformation; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: D010456:Peptides, Cyclic; D018027:Receptors, Glucagon; D011092:Polyethylene Glycols; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP