Author/Editor | Clemmensen, Christoffer; Chabenne, Joseph; Finan, Brian; Sullivan, Lorraine; Fischer, Katrin; Küchler, Daniela; Sehrer, Laura; Klančič, Teja; Hofmann, Susanna M.; Schriever, Sonja C. | |
Title | GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet | |
Type | članek | |
Vol. and No. | Letnik 63, št. 4 | |
Publication year | 2014 | |
Volume | str. 1422-1427 | |
ISSN | 0012-1797 - Diabetes | |
Language | eng | |
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. | |
Keywords | leptin debelost endokrinologija leptin obesity endocrinology |