TY - JOUR

T1 - GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet

AU - Clemmensen, Christoffer

AU - Chabenne, Joseph

AU - Finan, Brian

AU - Sullivan, Lorraine

AU - Fischer, Katrin

AU - Küchler, Daniela

AU - Sehrer, Laura

AU - Ograjsek, Teja

AU - Hofmann, Susanna M

AU - Schriever, Sonja C

AU - Pfluger, Paul T

AU - Pinkstaff, Jason

AU - Tschöp, Matthias H

AU - Dimarchi, Richard

AU - Müller, Timo D

PY - 2014/4

Y1 - 2014/4

N2 - 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.

AB - 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.

KW - Animals

KW - Diet, High-Fat

KW - Eating

KW - Feeding Behavior

KW - Glucagon

KW - Glucagon-Like Peptide 1

KW - Leptin

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Obese

KW - Obesity

KW - Polyethylene Glycols

KW - Receptors, Glucagon

KW - Weight Loss

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.2337/db13-1609

DO - 10.2337/db13-1609

M3 - Journal article

C2 - 24379349

VL - 63

SP - 1422

EP - 1427

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -