GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet
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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.
Original language | English |
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Journal | Diabetes |
Volume | 63 |
Issue number | 4 |
Pages (from-to) | 1422-7 |
Number of pages | 6 |
ISSN | 0012-1797 |
DOIs | |
Publication status | Published - Apr 2014 |
- Animals, Diet, High-Fat, Eating, Feeding Behavior, Glucagon, Glucagon-Like Peptide 1, Leptin, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Obesity, Polyethylene Glycols, Receptors, Glucagon, Weight Loss, Journal Article, Research Support, Non-U.S. Gov't
Research areas
ID: 186640652