PuSH - Publication Server of Helmholtz Zentrum München: GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet.

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Clemmensen, C. ; Chabenne, J.* ; Finan, B. ; Sullivan, L.* ; Fischer, K. ; Küchler, D. ; Sehrer, L. ; Ograjsek, T. ; Hofmann, S. ; Schriever, S.C. ; Pfluger, P.T. ; Pinkstaff, J.K.* ; Tschöp, M.H. ; DiMarchi, R.* ; Müller, T.D.

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

Diabetes 63, 1422-1427 (2014)

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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.

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