The incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1), are gut-derived peptides released in response to ingested nutrients that mediate important actions on nutrient metabolism. GLP-1 receptor agonists have been developed for the treatment of obesity independent of type 2 diabetes. Paradoxically, Glp1r-/- mice are protected against diet-induced obesity. Svendsen et al. hypothesized that developmental compensations might be present in animals with germ-line deletions of the incretin receptors. Therefore, they used acute pharmacologic antagonism in fully developed animals, but still found decreases in body weight under a high fat diet.
Pharmacological antagonism of the incretin system protects against diet-induced obesity
Objective: Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested.
Methods: We blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition.
Results: Antagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists.
Conclusions: Disruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.