GLP-1/Glucagon Coagonism Restores Leptin Responsiveness in Obese Mice Chronically Maintained on an Obesogenic Diet
- Christoffer Clemmensen1,
- Joseph Chabenne2,
- Brian Finan1,
- Lorraine Sullivan2,
- Katrin Fischer1,
- Daniela Küchler1,
- Laura Sehrer1,
- Teja Ograjsek3,
- Susanna M. Hofmann3,
- Sonja C. Schriever1,
- Paul T. Pfluger1,
- Jason Pinkstaff2,
- Matthias H. Tschöp1⇑,
- Richard DiMarchi4⇑ and
- Timo D. Müller1
- 1Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
- 2Ambrx, Inc., San Diego, CA
- 3Institute for Diabetes and Regeneration, Helmholtz Center Munich, German Research Center for Environmental Health, Ludwig-Maximilian University Munich, Munich, Germany
- 4Department of Chemistry, Indiana University, Bloomington, IN
- Corresponding authors: Matthias H. Tschöp, , and Richard DiMarchi, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1609/-/DC1.
- Received October 18, 2013.
- Accepted December 18, 2013.
- © 2014 by the American Diabetes Association.
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