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.
The point-counterpoint articles published in this issue of Diabetes deliberate the rationale for agonizing the glucose-dependent insulinotropic polypeptide receptor (GIPR) (1) or antagonizing the GIPR (2) in consideration of therapeutic approaches to treating obesity. The case for agonism is founded on substantial preclinical and clinical data, bolstered by the clinical efficacy of tirzepatide (3,4), a co-agonist for both the GIPR and glucagon-like peptide 1 receptor (GLP-1R) (5). The authors point to the actions of GIPR agonism to enhance insulin secretion, improve insulin sensitivity, and reduce inflammation in adipose tissue, as well as independent and combined effects with GLP-1R agonism in the brain to reduce food intake and decrease aversive responses, as supporting evidence for GIPR agonism.
On the other side, support for GIPR antagonism comes from loss-of-function genetics in mice and human studies of GIPR variants with impaired activity that associate with reduced body mass, along with preclinical studies and emerging human data demonstrating that chronic GIPR antagonism resists weight gain and enhances the weight-lowering effects of GLP-1R agonism. The conundrum that we attempt to resolve is how two diametrically opposing pharmacological approaches can produce the same outcome of reducing body weight. Layered into this discussion are the factors beyond weight loss that should be considered in deciding the relative merits of these two approaches. Resolving some of these unanswered questions will require additional experimentation, as well as the results of forthcoming clinical trials. Herein, we discuss GIPR agonism versus antagonism in the context of metabolic disease therapeutics.
The current major focus for comparing the results of GIPR agonism versus antagonism is weight loss. GIPR monoagonism reduces food intake and body weight in preclinical models (6) and in humans (7). Studies in mice reveal that GIPR agonism requires engagement with GIP receptors within the central nervous system (CNS) to lower body weight (8). Interestingly, deletion of GIPR alone in the mouse CNS also provides protection against diet-induced obesity (8), recapitulating the phenotype exhibited by the high-fat diet–fed whole-body–Gipr knockout mouse (9). Collectively, these observations capture the confusion in directional targeting of the GIPR, with both gain- and loss-of-function strategies decreasing body weight.
To establish precisely where the key GIPR-dependent signaling cascades occur within the CNS that are coupled with reduction of food intake, further resolution is required, with potential targets including neurons in the hypothalamus, hindbrain, and nonneuronal populations that potentially govern activity in these areas (10–14). Whether GIPR agonism and antagonism in each of these areas differentially suppress food intake through overlapping or distinct pathways remains unclear. One focus of particular interest is the collection of GABAergic neurons in the hindbrain. Here, GIPR agonism elicits antiaversive effects in the context of a range of noxious or aversive stimuli, including GLP-1R agonism (Fig. 1 A) (12,15,16). These antiaversive effects target populations of neurons different from those transducing anorectic signals and appear to translate to healthy human participants treated with a single dose of a long-acting GIP analog together with liraglutide (17). This points to an inhibitory tone originating from GIPR+ neurons to dampen the activity of GLP-1R neurons responsible for transducing aversive signals. Alternatively, GIPR agonism may attenuate aversive responses downstream of GLP-1R neurons.
Interestingly, deletion of Gipr in GABAergic neurons enhances the activity of GLP-1R agonism to reduce food intake and body weight and these GABAergic neurons are also critical for the enhanced weight loss activity of dual incretin agonists in comparison with GLP-1R monoagonism (14). In these same studies loss of the antiaversive properties of GIPR agonism in GABAergic neurons was also reported. Hence, we can surmise that one potential mechanism of basal GIPR activity in the hindbrain is to inhibit the satiating effects of GLP-1R agonism. Reducing this inhibitory tone, potentially through naturally occurring human GIPR variants with reduced signaling properties, or via pharmacological GIPR antagonism, could enhance the activity of anorectic GLP-1R signaling pathways, thereby increasing the sensitivity to and effectiveness of endogenous GLP-1 or pharmacological GLP-1R agonism (Fig. 1 B and C). This hypothesis aligns with reports of effective weight loss with bispecific molecules that simultaneously block GIPR while activating the GLP-1R (18–20). Theoretically, this approach of using GIPR antagonism might reduce the tolerability of simultaneous GLP-1R agonism (Fig. 1 B), a hypothesis currently being examined in clinical trials with maritide, a GIPR antagonist antibody conjugated to two peptide GLP-1R agonists.
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.
Two complementary studies provide further evidence linking attenuation of GIPR signaling to augmentation of GLP-1R pathways in the CNS. Gutgesell et al. (21) demonstrate a requirement for GLP-1R signaling to achieve the maximal effects of GIPR antagonism for reduction of food intake and body weight in mice. Furthermore, the anorectic actions of GIPR antagonism were preserved in mice with selective deletion of the Gipr in CNS GABAergic neurons or deletion of Gipr in the peripheral nervous system within peripherin-expressing neurons. Interestingly, gene expression profiles in hindbrain CNS neurons, notably, pathways linked to regulation of synaptic plasticity, exhibited similar patterns of modulation after acute GIPR antagonism versus GLP-1R agonism. Collectively, these findings, together with data from Wean et al. (14), highlight roles for the GLP-1R in the transduction of CNS signals emanating from genetic loss of GIPR signaling or pharmacological GIPR antagonism.
