The area postrema: a critical mediator of brain–body interactions

In this Outlook, van de Lisdonk and Li discuss the important role of area postrema neurons in communicating signals and responses between the body periphery and the brain, highlighting how they contribute to metabolic disorders and can be leveraged into innovative therapeutic strategies.

Abstract

The dorsal vagal complex contains three structures: the area postrema, the nucleus tractus solitarii, and the dorsal motor nucleus of the vagus. These structures are tightly linked, both anatomically and functionally, and have important yet distinct roles in not only conveying peripheral bodily signals to the rest of the brain but in the generation of behavioral and physiological responses. Reports on the new discoveries in these structures were highlights of the symposium. In this outlook, we focus on the roles of the area postrema in mediating brain–body interactions and its potential utility as a therapeutic target, especially in cancer cachexia.

It is increasingly recognized that a deeper investigation into how the central nervous system (CNS) and peripheral organs or tissues functionally interact is needed for a better understanding of many diseases, including cancer, metabolic disorders, immune disorders, infectious diseases, cardiovascular disorders, and psychiatric disorders. The area postrema (AP) is emerging as a critical mediator of the interactions between the CNS and the periphery, with dysfunctions potentially contributing to many of those diseases. The 88th CSHL Symposium on Quantitative Biology provided a timely forum for in-depth discussions on some of the new discoveries regarding the function of the AP (including those from the laboratories of Bo Li and Vineet Augustine, for example) and the possibility of this structure serving as a therapeutic target.

The AP has long been known as a chemoreceptor trigger zone for vomiting (Miller and Leslie 1994). It is located at the caudal end of the fourth ventricle in the brainstem and is uniquely positioned outside of the blood–brain barrier (BBB), allowing it to detect blood-borne emetic agents; it is furthermore involved in triggering nausea and vomiting in response to such agents (Borison 1989; Miller and Leslie 1994; Price et al. 2008; Zhang et al. 2021). Recent studies have begun to unravel the diverse cell types in the AP and the unique functions that they subserve. For example, glucagon-like peptide 1 receptor (Glp1r)-expressing neurons are the major excitatory neuronal type in the AP (Zhang et al. 2021), which contains a subpopulation of neurons expressing Gfral (Lerner et al. 2016; Suriben et al. 2020; Zhang et al. 2021; Sun et al. 2024). Notably, Gfral-expressing neurons are localized exclusively within the AP and the adjacent nucleus tractus solitarius (NTS) (Emmerson et al. 2017; Hsu et al. 2017; Mullican et al. 2017; Yang et al. 2017), with Gfral being the only known receptor for growth/differentiation factor 15 (GDF15) (Emmerson et al. 2017; Hsu et al. 2017; Mullican et al. 2017; Yang et al. 2017), a stress response cytokine and transforming growth factor β family protein that has been implicated in many diseases, including inflammatory diseases, tissue injury, cardiovascular diseases, cancer cachexia, and others (Bootcov et al. 1997; Johnen et al. 2007; George et al. 2016; Tsai et al. 2018; Luan et al. 2019).

GDF15 is only weakly expressed in most tissues under normal conditions but is strongly induced in disease conditions (Fairlie et al. 1999; Mullican et al. 2017; Tsai et al. 2018). Activation of the GDF15/Gfral signaling pathway causes emesis and nausea, leading to anorexia (Johnen et al. 2007; Altena et al. 2015; Lerner et al. 2016; Tsai et al. 2018; Breen et al. 2020; Zhang et al. 2021). In addition, activation of Gfral-expressing neurons drives aversive effects and anorexia in mice (Hsu et al. 2017; Borner et al. 2020; Sabatini et al. 2021), whereas inhibition of Gfral-expressing neurons in the AP (Sun et al. 2024) or inhibition of GDF15/Gfral signaling (Lerner et al. 2016; Suriben et al. 2020) attenuates cancer cachexia in animal models. Therefore, Gfral-expressing neurons—and specifically the GDF15/Gfral signaling pathway in these neurons—have been explored as a potential target for treating metabolic disorders, including cancer cachexia and obesity (Tsai et al. 2018, 2019; Borner et al. 2020; Breit et al. 2023; Chelette et al. 2023; Kanta et al. 2023; Engström Ruud et al. 2024).

AP neurons and bodyweight regulation in cancer cachexia and obesity

Cancer cachexia is a severe metabolic syndrome characterized by anorexia, fatigue, and dramatic involuntary bodyweight loss (Fearon and Carter 1988; Fearon et al. 2012; Baracos et al. 2018; Biswas and Acharyya 2020). It is associated with up to 80% of cancer patients, who essentially die of cachexia instead of cancer itself (Fearon et al. 2013; Baracos et al. 2018). Decades of studies indicate that interleukin-6 (IL-6) plays a critical role in cancer cachexia (Stephens et al. 2008; Tan et al. 2011; Fearon et al. 2012, 2013; Narsale and Carson 2014; Baracos et al. 2018; Biswas and Acharyya 2020). However, until recently, how IL-6 contributes to the development of cachexia symptoms had remained elusive. A recent study identifies neurons in the AP as the critical mediator of IL-6 function that leads to cancer cachexia in multiple mouse models and further suggests that an “AP network”—which encompasses the AP, the nucleus tractus solitarii (NTSs), the parabrachial nucleus (PBN), the paraventricular nucleus of the hypothalamus (PVN), the bed nucleus of the stria terminalis (BNST), and the central amygdala (CeA)—is involved in the generation of cachectic symptoms (Sun et al. 2024).

Most of the structures within the AP network are directly connected with each other either reciprocally or unidirectionally (Dong et al. 2001a,b; Song et al. 2009; Roman et al. 2016; Palmiter 2018; Zhang et al. 2021). All these structures show elevated activity when IL-6 starts to elevate in the AP during cancer progression, with the hyperactivity persisting until a cachectic state is reached in different cancer models. Notably, this cancer-induced AP network hyperactivity can be mimicked by intravenous injection of IL-6. Previous studies show that inflammation, which typically results in increased IL-6, can also induce hyperactivity in this network (Ilanges et al. 2022; Florsheim et al. 2023). Thus, IL-6 acts as a messenger to the AP network, conveying information about the peripheral inflammatory status (including that associated with tumor growth).

Some of the structures, such as the PBN and PVN, have been previously shown to mediate the anorexia phenotypes in cancer cachexia (Lerner et al. 2016; Campos et al. 2017; Suriben et al. 2020; Olson et al. 2021), consistent with findings that these structures drive feeding suppression (Grossberg et al. 2010; Pei et al. 2014; Roman et al. 2016; Campos et al. 2017; Chen et al. 2018; Palmiter 2018; Sabatini et al. 2021; Yoo et al. 2021; Zhang et al. 2021; Xie et al. 2022). The AP also participates in anorexia in cancer cachexia (Sun et al. 2024). As the AP sends direct projections to the PBN and the NTS, and the NTS also directly projects to the PBN as well as the PVN (Song et al. 2009; Zhang et al. 2021; Xie et al. 2022), it is likely that the AP drives anorexia in cachexia through the PBN and PVN. Besides anorexia, the AP appears to also drive weight loss in the absence of feeding suppression during cancer progression (Sun et al. 2024), an observation consistent with previous findings that cancer cachexia involves active catabolic processes and can only be partially alleviated by nutritional support (Fearon et al. 2013; Baracos et al. 2018; Biswas and Acharyya 2020). This function of the AP could be mediated at least in part by the neural circuits linking structures in the AP network with peripheral organs (Morrison 1999; Nandi et al. 2002; Deuchars and Lall 2015; Cardoso et al. 2021; Papazoglou et al. 2022). Future studies will elucidate how the AP network drives both anorexia and catabolism in cancer cachexia.

Because activation of Gfral-expressing neurons results in anorexia, they have also emerged as a potential target for obesity treatment (Hsu et al. 2017; Tsai et al. 2018; Patel et al. 2019; Borner et al. 2020; Sabatini et al. 2021). As these neurons constitute a subpopulation of Glp1r-expressing neurons in the AP (Lerner et al. 2016; Suriben et al. 2020; Zhang et al. 2021; Sun et al. 2024), it is interesting to note that GDF15 and GLP-1 peptides may synergistically suppress food intake (Frikke-Schmidt et al. 2019). As mentioned above, neurons in the AP promote catabolism independent of food intake; therefore, it is possible that Gfral-expressing neurons or GDF15/Gfral signaling in the AP also promote(s) peripheral catabolism, thereby reducing obesity. Consistent with this idea, GDF15 promotes lipolysis, oxidative metabolism, and thermogenesis, helping reduce inflammation and insulin resistance in obesity (Chrysovergis et al. 2014; Engström Ruud et al. 2024). In addition, a recent study indicates that GDF15 mediates the beneficial effects of metformin on energy balance and body weight regulation, including its influence on metabolic rate (Coll et al. 2020).

AP neurons and bodily physiology

The immune system and the brain have extensive cross-talk (Pavlov et al. 2018). Cytokines, such as GDF15, IL-6, IL-1, and tumor necrosis factor-α (TNF-α), are key mediators of immune responses. They can inform the brain about the physiological status of the body through interacting with the vagus nerve, entering circumventricular organs lacking a BBB (e.g., the AP) or, in some cases, crossing the BBB, thereby influencing brain function (Pavlov et al. 2018). Notably, the interactions between the AP and the immune system can support highly specific functions. For example, it has recently been shown that GDF15/Gfral signaling mediates the development of allergic sensitization-driven antigen-specific avoidance behavior (Florsheim et al. 2023). How such specificity is achieved remains to be elucidated.

Traditionally, most literature has concentrated on how cytokines and hormones influence brain function. These molecules, often produced in response to various physiological states such as stress, infection, or metabolic changes, have significant effects on the CNS, impacting behavior, mood, and appetite (Wallenius et al. 2002; Kawai et al. 2021). More recent studies have uncovered that the opposite is also true; that is, the brain has surprisingly powerful control over peripheral immunity and metabolism. For instance, a recent study showed that a population of NTS neurons tightly modulates the course of the peripheral immune response, including both proinflammatory and anti-inflammatory responses (Jin et al. 2024). It will be interesting to determine the role of the AP in this process, as the AP is tightly connected with the NTS and shows hyperactivity during peripheral inflammation (Jin et al. 2024). Another example of how the brain controls peripheral physiology is that GDF15/Gfral signaling in the AP coordinates tolerance to inflammatory damage through regulation of triglyceride metabolism (Luan et al. 2019).

The AP also directly communicates with the cardiovascular system via vagal sensory neurons (VSNs). A recent study showed that VSNs expressing neuropeptide Y receptor Y2 (NPY2R) connect the heart ventricular wall to the AP and that activation of NPY2R-expressing VSNs elicits Bezold–Jarisch reflex responses (hypotension, bradycardia, and suppressed respiration) and causes an animal to faint, a phenomenon that mimics clinical syncope (Lovelace et al. 2023). However, how AP neurons regulate cardiovascular function under physiological conditions and how they become dysfunctional and contribute to syncope are unclear.

A way forward

The AP is emerging as a promising therapeutic target for treating metabolic disorders, in particular cancer cachexia and obesity. In this regard, the GDF15/Gfral signaling pathway has received the most attention. However, as GDF15 appears to function as a bodily alarm that triggers adaptive responses to a broad range of insults (Luan et al. 2019; Lockhart et al. 2020), blocking GDF15/Gfral signaling will likely have adverse effects. Targeting other signaling pathways in these neurons, such as IL-6-mediated signaling (Sun et al. 2024), may avoid such side effects. In addition, the AP does not function on its own but rather acts in concert with other structures in the AP network, including the NTS, PBN, PVN, BNST, and CeA, to regulate feeding behavior and peripheral metabolic processes. Future studies are warranted to investigate how these structures coordinate their functions under different metabolic conditions and what their specific roles are in metabolic disorders. Another important direction is to elucidate how different classes of AP neurons work together to carry out the rather specific roles of the AP in regulating feeding behavior, antigen-specific avoidance, metabolism, and immune function.

The symposium has sparked important conversations, and it is now up to the research community to build on these ideas and drive the field forward. By continuing to explore the interplay between the brain and the body, we hope to uncover new pathways for intervention and ultimately improve the health and well-being of individuals struggling with metabolic disorders and beyond.