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

Abstract

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.

Pharmacological Approaches in the Treatment and Maintenance of Weight Loss

“…PEGylated (PEG) leptin, along with PEG-GLP-1/glucagon, may be another potential combination therapy option (66). This combination is an intriguing potential option, as preclinical data indicate that PEG-leptin and PEG-GLP-1/ glucagon coagonism can restore leptin responsiveness, which is often reduced when leptin is used alone.…”

“…Responsiveness to leptin is associated with decreased food intake, improved glucose tolerance, and insulin sensitivity, as well as decreased triglycerides and lower plasma cholesterol. These may be the contributing factors that lead to the weight loss observed with leptin/GLP-1/ glucagon coagonism (66).…”

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

“…Polyethylene glycolated (PEG)-leptin, along with PEG-GLP-1/glucagon, may be another potential combination therapy option (102). This combination is an intriguing potential antihyperglycemic option, because preclinical data indicate that PEG-leptin and PEG-GLP-1/glucagon coagonism can restore leptin responsiveness, which is often reduced when leptin is used alone.…”

Renaissance of leptin for obesity therapy

“…In 2009, this strategy was used to show that a molecule with balanced action at the glucagon receptor and the GLP-1 receptor (GLP-1R), synergistically orchestrates distinct biological pathways to exhibit a coordinated effect on energy metabolism in rodents [59]. This GLP-1R/glucagon receptor coagonist was recently found to act as a powerful leptin sensitiser in leptin-resistant DIO mice [60]. Indeed, animals who received co-treatment with GLP-1/glucagon and leptin exhibited superior weight loss relative to each monotherapy.…”