Glucose‐dependent insulinotropic polypeptide receptor systems in the hypothalamus and the brainstem regulate feeding and weight through distinct pathways

Abstract

The report by Adriaenssens et al. in JCI Insight 22 May 2023 explored the role and property of the neurons that express glucose‐dependent insulinotropic polypeptide receptor (GIPR) in the brainstem and hypothalamus. The chemogenetic activation of the brainstem GIPR neurons and that of the hypothalamic GIPR neurons showed different feeding and behavior responses. The brainstem GIPR neurons projected to the paraventricular hypothalamus and lateral parabrachial nucleus. Fluorescent‐labeled, stabilized peptide GIPR agonist (GIPRA), peripherally injected, localized to the area postrema, nucleus tractus solitarius, median eminence and arcuate hypothalamus. This report showed the role of brainstem GIPR neurons in receiving GIPRA to drive the neural circuit to reduce feeding and bodyweight. In this commentary, distinct and possible cooperative roles of the hypothalamic and the brainstem GIPR pathways will also be discussed.

This report showed the role of brain stem glucose‐dependent insulinotropic polypeptide receptor (GIPR) neurons in receiving GIPR agonist (GIPRA) to drive the neural circuit to reduce feeding and bodyweight. In this commentary, distinct and possible cooperative roles of the hypothalamic and brainstem pathways will also be discussed.

The report by Adriaenssens et al. ¹ in JCI Insight 22 May 2023 explored the role and property of the neurons that express glucose‐dependent insulinotropic polypeptide (GIP) receptor (GIPR), GIPR neurons, in the brainstem and hypothalamus.

GIP and glucagon‐like peptide‐1 (GLP‐1) are the incretin hormones that are released from, respectively, K and L cells in the small intestine on ingestion of meals, and augment postprandial insulin release from pancreatic β‐cells. The effect of GIP and the GIP receptor agonists (GIPRAs) has been highly controversial, including elevation and reduction of food intake, bodyweight, and adiposity. Hence, GIP has not been considered the target for treating obesity. Recently, preclinical and clinical studies have placed GIPR signaling as an effective cotarget when combined with GLP‐1 receptor agonists (GLP‐1RAs) for enhancing weight loss, as well as glycemic control. In GIPR/GLP‐1R coagonism, the resultant marked weight loss correlates with the reduction of food intake, a process regulated by the central nervous system (CNS). Central nervous system expression of Gipr is necessary for the synergistic weight loss by GIPR/GLP1R coagonism. Gipr‐expressing populations localize to regions of the central nervous system that control eating, including the paraventricular hypothalamus, arcuate hypothalamus (ARH) and dorsomedial hypothalamus in the hypothalamus, and the area postrema (AP) and nucleus tractus solitarius (NTS) in the dorsal vagal complex (DVC). However, the relative contributions of Gipr cells within these brain regions to the control of feeding behavior are incompletely characterized.

Adriaenssens et al. ¹ explored the role and property of the GIPR neurons in the DVC and hypothalamus. For this, the authors used various methods, including brain region‐specific deletion and activation of GIPR cells, tracing the projection of these neurons, analysis of gene expression in these neurons, and use of fluorescence labeled GIPRA, to explore the target area of the peripherally injected GIPRA. They found that GIPR neurons are localized in the AP and NTS in the DVC, and in the ME and ARH in the hypothalamus. They created the DVC‐specific GIPR‐knockout (KO) mice (Gipr ^{Δ DVC}‐KO mice) and the hypothalamus‐specific Gipr‐KO mice (Gipr ^{Δ Hyp}‐KO mice) by stereotaxically injecting recombinant adeno‐associated virus ‐ cyclization recombination enzyme (rAAV‐Cre) into the DVC and hypothalamus of Gipr ^fl/fl mice.

Diet‐induced obese wild‐type (WT) and Gipr ^{Δ Hyp} mice both lost weight when treated with the long‐acting GLP‐1RA, GLP‐140, in which Gipr ^{Δ Hyp} mice tended to lose more weight compared withWT mice. WT and Gipr ^{Δ Hyp} mice responded to the add‐on administration of long‐acting GIPRA, GIP‐085, with further reductions in food intake and weight loss. These data suggested that fully intact hypothalamic Gipr expression is not required for the synergistic weight loss and anorectic activity induced by GIPR/GLP1R coagonism, suggesting a role of DVC Gipr expression.

The authors studied the systemic roles of the DVC GIPR neurons and the hypothalamic GIPR neurons. The chemogenetic activation of DVC GIPR neurons and that of hypothalamic GIPR neurons showed different phenotypes. The former induced greater inhibition of food intake than the latter. The former decreased ambulatory activity and energy expenditure, whereas the latter increased them. Furthermore, the activation of DVC GIPR neurons induced conditioned taste aversion, the behavior that corresponds to nausea and emesis in humans (Figure 1). These results show distinct modes for the hypothalamic GIPR neurons and DVC GIPR neurons in their action to suppress feeding: hypothalamic GIPR neurons reduce bodyweight principally by inhibiting appetite, whereas DVC GIPR neurons reduce bodyweight by inhibiting appetite and altering behaviors, including conditioned taste aversion (Figure 1).

Figure 1.

Glucose‐dependent insulinotropic polypeptide receptor (GIPR)‐expressing cells in the hypothalamus and brainstem, and their roles in controlling feeding and bodyweight. (2) and (3): The presence or function of GIPR is suggested by References (2) and (3), respectively. GLP1R, glucagon‐like peptide‐1 receptor.

The projection of the DVC GIPR neurons was studied. The NTS Gipr neurons in the DVC projected to the paraventricular hypothalamus and, to a lesser extent, the lateral parabrachial nucleus (Figure 1). These are the areas that receive the projection from the ARH neurons, and serve as the integral center for feeding and metabolism. Therefore, it is likely that the hypothalamic GIPR neuron pathway and the DVC GIPR neuron pathway activated by GIPRA merge in the paraventricular hypothalamus and possibly the parabrachial nucleus, and thereby act cooperatively (Figure 1).

The authors claim that the hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP‐1R coagonism on food intake and bodyweight. However, by scrutinizing the data, the effects of GLP‐1RA and GIPRA on bodyweight and food intake were substantially different between WT and Gipr ^{Δ Hyp}‐KO mice, suggesting that the hypoyjalamic Gipr does some work. The role of the hypothalamic Gipr in the synergistic effect of GIPR/GLP‐1R coagonism on bodyweight and feeding needs to be carefully examined. In fact, Hang et al. ² has recently shown that GIPRA directly interacts with the ARH proopiomelanocortin (POMC) neurons and GLP‐1‐responsive neurons to induce Ca²⁺ signaling, an action possibly implicated in the feeding‐ and weight‐lowering action of GIPRA. This report also indicates that the ARH POMC neurons most likely express GIPR, as well as GLP‐1R (Figure 1).

Notably, the authors designed fluorescent‐labeled, stabilized GIPR peptide agonist probes, sGIP549 and sGIP648, and showed that GIP648 localized to the AP and ME, and to a lesser extent, NTS and ARH regions. The AP/NTS and ME/ARH areas have been considered the regions where the blood–brain barrier is relatively leaky. Therefore, neurons in these areas could be accessed by peripherally injected GIPRA, and serve as direct targets for its feeding‐ and weight‐lowering action of GIPRA (Figure 1). Notably, it has recently been shown that GLP‐1RA is shuttled to target cells in the hypothalamus by specialized ependymoglial cells called tanycytes located in the third ventricle in the ME region, bypassing the blood–brain barrier ³ (Figure 1). The tanycyte machinery could also shuttle GIPRA.

The present study showed that the activation of DVC GIPR neurons induces conditioned taste aversion, the behavior that corresponds to nausea/emesis in humans. In contrast, it was previously reported that GIPR signaling in DVC blocks emesis and attenuates illness behaviors elicited by GLP‐1R activation, while maintaining reduced food intake, bodyweight loss and improved glucose tolerance ⁴ . Whether GIPR signaling in DVC induces emesis or not, and whether it attenuates emesis elicited by GLP‐1R agonism are of importance in regard to the safety of the GIPR/GLP‐1R coagonism and remain to be clarified.

The authors carried out transcriptomic characterization of Gipr‐expressing cells in the brainstem. The majority of Gipr‐expressing cells coexpressed the neuronal markers, such as Syt1 (Figure 1). They found that the brainstem Gipr ^EYFP+ neurons substantially express markers of both glutamatergic (Slc17a6) and gamma amino butyric acidergic (Slc32a1) cells. They carried out differential gene expression analysis to compare and contrast markers that characterize Gipr ^NTS versus Gipr ^AP neurons, and found highly distinct expression patterns between Gipr ^NTS versus Gipr ^AP neurons.

Gipr ^EYFP+ neurons were enriched for transcripts encoding the neuropeptides natriuretic peptide C (Nppc) and proenkephalin (Penk), and protein kinase C δ (Prkcd). In contrast, Glp1r ^EYFP+ neurons were enriched for the neuropeptides prepronociceptin (Pnoc) and proopiomelanocortin (Pomc), as well as the thyroid hormone transporter transthyretin (Ttr).

The authors found that Gipr ^EYFP+ and Glp1r ^EYFP+ populations of the brainstem are largely separate and distinct, suggesting that the brainstem is not the major site for cooperation between GIPRA and GLP‐1RA. In the hypothalamus, in contrast, Hang et al. ² reported that GIPRA activates the ARH POMC neuron, a well‐known responder to GLP‐1 (Figure 1), supporting that Gipr populations and Glp1r populations might partly overlap in the hypothalamic ARH. However, in Gipr ^{Δ Hyp} mice, GIPRA enhanced the GLP‐1RA‐induced reductions in food intake and bodyweight ¹ . Therefore, the central site for cooperation between GIPRA and GLP‐1RA for feeding‐ and weight‐reduction remains to be defined.

DISCLOSURE

Animal studies: Approval of the research protocol: Animal experiments were carried out after receiving approval from the Institutional Animal Experiment Committee and in accordance with the Institutional Regulation for Animal Experiments at Gifu University (IACUC approval number: 2021‐235).