Glucagon-like peptide-1 receptor (GLP-1R) agonists have transformed obesity pharmacotherapy, producing clinically meaningful weight loss and robust improvements in glycemic control. Yet their efficacy remains constrained by dose-limiting gastrointestinal adverse effects, including nausea and vomiting, that reduce adherence and limit escalation to maximally effective doses. Thus, the next-generation of obesity therapeutics must not only enhance weight loss but also expand the therapeutic window by dissociating metabolic efficacy from aversive side effects. The recent clinical success of dual GLP-1R/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has catalyzed renewed interest in GIP biology. However, this resurgence has exposed a fundamental paradox: both pharmacological activation and blockade of GIP receptor (GIPR) signaling reduce body weight and enhance the efficacy of GLP-1-based therapies. These seemingly opposing pharmacological strategies therefore converge on a shared therapeutic outcome through distinct biological mechanisms. GIPR agonism appears to promote weight loss in part through recruitment of anorectic neural circuits, increased thermogenesis, and attenuation of GLP-1-induced aversive effects, whereas GIPR antagonism may enhance GLP-1R signaling and counteract the lipogenic actions of endogenous GIP. In this review, we examine the mechanistic basis underlying the GIPR agonism-antagonism paradox and discuss how GIPR signaling may regulate the balance between metabolic efficacy and treatment tolerability. Understanding these mechanisms may guide the rational design of next-generation incretin-based therapies that maximize weight loss while minimizing adverse effects.
