Therapeutic Targeting of the GIP Receptor-Revisiting the Controversies

Abstract

Current and emerging strategies to therapeutically target weight management include pairing agonism of the glucagon-like peptide 1 receptor (GLP-1R) with either agonism or antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR). On the surface, these two approaches seem contradictory, yet they have produced similar effects for weight loss in clinical studies. Arguments that support the rationale for both approaches are made in these point-counterpoint articles, founded on preclinical studies, human genetics, and clinical outcomes. Here, we attempt to reconcile how two opposing approaches can produce similar effects on body weight by evaluating the leading hypotheses derived from the available evidence.

Figure 1

Hypotheses on how GIPR agonism or antagonism regulates body weight. A: GIPR agonism increases the activity of GABAergic inhibitory neurons in the hindbrain regions of the CNS. The increase in inhibitory tone may decrease food intake, independently adding to the actions of GLP-1R agonism. GIPR⁺ neurons have also been shown to project onto, and inhibit, GLP-1R⁺ GLUTamatergic neurons that produce the aversive effects in response to GLP-1R agonism. B: GIPR antagonism may decrease the activity of GABAergic inhibitory neurons, leading to disinhibition of the GLP-1R⁺ neurons in the hindbrain that decrease food intake. As a result, GIPR antagonism increases the effectiveness of GLP-1R agonism to decrease food intake. C: Chronic loss of GIPR activity, potentially achieved by either genetic or pharmacological loss of function, produces an increase in GLP-1R sensitivity. In β-cells, which express both GIPR and GLP-1R, this may theoretically occur in a cell-autonomous manner. As very few neuronal populations express both receptors, this mechanism is more likely explained by a decrease in the interaction between distinct GIPR⁺ and GLP-1R⁺ neurons in the CNS. Loss of GIPR neuronal activity disinhibits GLP-1R⁺ neurons, increasing their activity. D: Chronic agonism of the GIPR drives desensitization to result in loss of function that resembles antagonism. Although this hypothesis would provide a harmonious explanation to reconcile the effects of GIPR agonism and antagonism, there is currently no evidence to suggest that tirzepatide attenuates activity in GIPR⁺ neurons that regulate food intake. GLP-1RA, GLP-1 receptor agonist.