title: GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet.
abstract: We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an ∼15% body weight loss, upon which they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an ∼18% greater weight loss as compared with PEG-GLP-1/glucagon alone and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 cotreatment. In summary, we report that GLP-1/glucagon coagonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy for the treatment of obesity and diabetes.
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Clemmensen
authors.forename: Joseph
authors.initials: J
authors.lastname: Chabenne
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.forename: Lorraine
authors.initials: L
authors.lastname: Sullivan
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.forename: Daniela
authors.initials: D
authors.lastname: Küchler
authors.forename: Laura
authors.initials: L
authors.lastname: Sehrer
authors.forename: Teja
authors.initials: T
authors.lastname: Ograjsek
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Hofmann
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Schriever
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Jason
authors.initials: J
authors.lastname: Pinkstaff
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Richard
authors.initials: R
authors.lastname: Dimarchi
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005934:Glucagon / Q000819:agonists / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000627:therapeutic use*; D020738:Leptin / Q000819:agonists* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D018027:Receptors, Glucagon / Q000819:agonists*; D015431:Weight Loss
chemical_list: D020738:Leptin; D018027:Receptors, Glucagon; D011092:Polyethylene Glycols; D052216:Glucagon-Like Peptide 1; D005934:Glucagon