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- Title
GLP-1/Glucagon Coagonism Restores Leptin Responsiveness in Obese Mice Chronically Maintained on an Obesogenic Diet.
- Authors
Clemmensen, Christoffer; Chabenne, Joseph; Finan, Brian; Sullivan, Lorraine; Fischer, Katrin; Küchler, Daniela; Sehrer, Laura; Ograjsek, Teja; Hofmann, Susanna M.; Schriever, Sonja C.; Pfluger, Paul T.; Pinkstaff, Jason; Tschöp, Matthias H.; DiMarchi, Richard; Müller, Timo D.
- 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.
- Subjects
LEPTIN; POLYETHYLENE; EXENDINS; PEPTIDES; GLUCAGON-like peptide 1; BODY weight
- Publication
Diabetes, 2014, Vol 63, Issue 4, p1422
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db13-1609