GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet

  1. Timo D. Müller1
  1. 1 Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) and Technical University Munich, Munich, Germany
  2. 2 Ambrx, Inc., San Diego, CA, USA 92037
  3. 3 Institute for Diabetes and Regeneration, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH) and Ludwig-Maximilian University Munich, Munich, Germany
  4. 4 Department of Chemistry, Indiana University, Bloomington, IN, US 47405
  1. *Corresponding authors: Matthias H. Tschöp, tschoep{at}, Richard D. DiMarchi, rdimarch{at}


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.

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