GLP-1/glucagon co-agonism 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 Hofmann3,
- Sonja S. Schriever1,
- Paul T. Pfluger1,
- Jason Pinkstaff2,
- Matthias H. Tschöp1,*,
- Richard DiMarchi4,* and
- Timo D. Müller1
- 1 Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) and Technical University Munich, Munich, Germany
- 2 Ambrx, Inc., San Diego, CA, USA 92037
- 3 Institute for Diabetes and Regeneration, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) and Ludwig-Maximilian University Munich, Munich, Germany
- 4 Department of Chemistry, Indiana University, Bloomington, IN, US 47405
- *Corresponding authors: Matthias H. Tschöp, , Richard D. DiMarchi,
We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically-optimized, PEGylated (PEG) leptin analog in combination with exendin-4 or FGF21. However, return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced co-agonism at the GLP-1 and glucagon receptors can restore leptin responsiveness in DIO mice maintained on HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce a ∼15% body weight loss, once upon 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 to 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 co-treatment. In summary, we report that GLP-1/glucagon co-agonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value this polypharmacotherapy for the treatment of obesity and diabetes.
- Received October 18, 2013.
- Accepted December 18, 2013.
- © 2013 by the American Diabetes Association.
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