👤 Bart C De Jonghe

The induction of nausea and emesis represents a significant barriers to optimizing weight loss medications for the treatment of obesity. Identifying mechanisms that improve tolerability and/or enhance efficacy without induction of emetic neurocircuitry could provide substantial therapeutic benefits. Candidate peptide YY (PYY)-based approaches for obesity treatment are no exception, as PYY-based therapeutics are uniformly associated with nausea and emesis. Recently, interest in glucose-dependent insulinotropic polypeptide receptor (GIPR)-based therapeutics has resurfaced, with some paradoxical findings from several preclinical studies showing that both GIPR agonism and antagonism, when combined with glucagon-like peptide-1 receptor (GLP-1R) agonists, result in greater body weight loss and superior glycemic control compared to GLP-1R agonism alone. Here, we investigated the effects of pharmacological modulation of the GIPR system on the actions of PYY. We found that systemic GIPR agonism attenuated PYY-induced malaise while preserving its anorectic and body weight-lowering effects in rats. Interestingly, GIPR antagonism enhanced PYY-induced hypophagia and body weight loss without compromising its malaise tolerability profile. Furthermore, inhibition of GIPR signaling significantly reduced PYY-induced c-Fos expression in the area postrema (AP) of the hindbrain. Since both NPY2R and GIPR are expressed in the same AP neurons, this suggests a potential neuronal pathway by which GIPR modulates the effects of PYY. Overall, our findings underscore the multifaceted actions of the GIPR system and highlight the therapeutic potential of both GIPR agonism and antagonism in enhancing and improving the effects of PYY-based obesity treatments. Show less

Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments. Show less

Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV. Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV. Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews. Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis. Show less

The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development of peptide YY (PYY)-based approaches to treat obesity are no exception, as PYY receptor agonism is often accompanied by nausea and vomiting. Here, we sought to determine whether glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist reduced conditioned taste avoidance (CTA) without affecting hypophagia mediated by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were found to be expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in detecting aversive stimuli. Peripheral administration of a GIPR agonist induced neuronal activation (cFos) in the AP. Further, whole-brain cFos analyses indicated that PYY-induced CTA was associated with augmented neuronal activity in the parabrachial nucleus (PBN), a brainstem nucleus that relays aversive/emetic signals to brain regions that control feeding behavior. Importantly, GIPR agonism reduced PYY-mediated neuronal activity in the PBN, providing a potential mechanistic explanation for how GIPR agonist treatment reduces PYY-induced nausea-like behavior. Together, the results of our study indicate a novel mechanism by which GIP-based therapeutics may have benefit in improving the tolerability of weight loss agents. Show less

Introduced less than two decades ago, glucagon-like peptide-1 receptor agonists rapidly reshaped the field of Type 2 diabetes mellitus (T2DM) care by providing glycaemic control in tandem with weight loss. However, FDA-approved GLP-1 receptor agonists are often accompanied by nausea and emesis and, in some lean T2DM patients, by undesired anorexia. Importantly, the hypophagic and emetic effects of GLP-1 receptor agonists are caused by activation of central GLP-1 receptors. This review summarizes two different approaches to mitigate the incidence and severity of nausea and emesis related to GLP-1 receptor agonists: conjugation with vitamin B Show less

Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting. Show less

Gastric inhibitory peptide (GIP) is best known for its role as an incretin hormone in control of blood glucose concentrations. As a classic satiation signal, however, the literature illustrates a mixed picture of GIP involvement with an at best weak anorectic response profile being reported for GIP receptor (GIPR) signaling. Not surprisingly, the pursuit of exploiting the GIP system as a therapeutic target for diabetes and obesity has fallen behind that of the other gastrointestinal-derived incretin, glucagon-like peptide 1 (GLP-1). However, recent discoveries highlighted here support potential therapeutic advantages of combinatorial therapies targeting GIP and GLP-1 systems together, with perhaps the most surprising finding that GIPR agonism may have antiemetic properties. As nausea and vomiting are the most common side effects of all existing GLP-1 pharmacotherapies, the ability for GIP agonism to reduce GLP-1-induced illness behaviors but retain (if not enhance) weight loss and glycemic control may offer a new era in the treatment of obesity and diabetes. Show less