A Contemporary Rationale for Agonism of the GIP Receptor in the Treatment of Obesity

Abstract

In combatting the obesity crisis, leveraging mechanisms that lower body weight is critical. The finding that treatment with tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, produces profound weight loss highlights the value of activating the incretin receptors. Supporting this, recent studies have revealed mechanisms by which GIP receptor (GIPR) activation is beneficial in pancreatic islets, the central nervous system (CNS), and adipose tissue. Paradoxically, a hypothesis has emerged that GIPR antagonism could be an additional option in treating obesity. This concept stems from concern that GIP facilitates lipid uptake and storage in adipose tissue, although the lipid-buffering capacity of adipocytes versus other cell types is metabolically favorable. In this article, we highlight the natural physiology of the incretins, noting GIP as the primary incretin. In the CNS, GIPR agonism attenuates nausea and suppresses appetite, features that also help GLP-1 receptor agonism promote a negative energy balance. Further, we provide rationale that, in protecting against ectopic fat distribution and augmenting substrate utilization to promote insulin sensitivity, GIPR activity in adipose tissue is advantageous. Collectively, these attributes support GIPR agonism in the treatment of obesity and metabolic disease.

Figure 1

The case for GIPR agonism is founded on the natural incretin actions of native GIP and bolstered by new findings showing agonist-driven effects in the brain and adipose tissue. A: Key clinical studies and preclinical mechanistic findings are indicated, highlighting discoveries since the initial report of the GIP and GLP-1 receptor agonist tirzepatide in 2018. B: Patent publications describing the discovery of compounds containing GIPR activity. GIP, glucose-dependent insulinotropic polypeptide; GIPRA, GIP receptor agonist; IR, insulin resistance; LAGIP, long-acting GIP; TZP, tirzepatide; WL, weight loss.

Figure 2

Potential mechanisms by which GIPR agonism may contribute to the efficacy of multireceptor agonism in weight management. In the CNS, GIPR agonism is implicated in the attenuation of nausea and the suppression of appetite, promoting a negative energy balance for sustaining weight loss. In adipose tissue, GIPR agonism improves lipid handling and augments BCAA catabolism, both of which are insulin sensitizing. Further, recent data from transgenic mice point to potential GIPR-mediated effects on energy expenditure via futile calcium cycling. GIPR, glucose-dependent insulinotropic polypeptide receptor; GLP-1R, glucagon-like peptide 1 receptor.