GLP-1/Glucagon Coagonism Restores Leptin Responsiveness in Obese Mice Chronically Maintained on an Obesogenic Diet

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) exp...

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Veröffentlicht in:Diabetes (New York, N.Y.) N.Y.), 2014-04, Vol.63 (4), p.1422-1427
Hauptverfasser: CLEMMENSEN, Christoffer, CHABENNE, Joseph, PFLUGER, Paul T, PINKSTAFF, Jason, TSCHOP, Matthias H, DIMARCHI, Richard, MÜLLER, Timo D, FINAN, Brian, SULLIVAN, Lorraine, FISCHER, Katrin, KÜCHLER, Daniela, SEHRER, Laura, OGRAJSEK, Teja, HOFMANN, Susanna M, SCHRIEVER, Sonja C
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Sprache:eng
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Zusammenfassung: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.
ISSN:0012-1797
1939-327X
DOI:10.2337/db13-1609