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

  1. Timo D. Müller1
  1. 1Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
  2. 2Ambrx, Inc., San Diego, CA
  3. 3Institute for Diabetes and Regeneration, Helmholtz Center Munich, German Research Center for Environmental Health, Ludwig-Maximilian University Munich, Munich, Germany
  4. 4Department of Chemistry, Indiana University, Bloomington, IN
  1. Corresponding authors: Matthias H. Tschöp, matthias.tschoep{at}, and Richard DiMarchi, rdimarch{at}


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.


  • Received October 18, 2013.
  • Accepted December 18, 2013.

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