Intermediary Brain Regions in Hunger and Appetite Control

Introduction

In the last article in this series I discussed various aspects of the hypothalamus and the hypothalamic nuclei that play integral roles in homeostatic food intake regulation. In this article I will discuss other brain regions that are significantly involved and work primarily with the hypothalamus or otherwise at a subconscious level. Thus, these are mostly intermediary regions that process various types of input before sending output to the conscious decision-making regions of the brain, and several of them participate in networks of signaling involving serotonin and dopamine. This will not be an exhaustive discussion of every single aspect of the brain, but rather a general overview of the more important components that influence food intake. Many of these regions contribute to hedonic food intake regulation as well; I will discuss this further in the next article.

I have included the brain regions I will discuss in the blue text in the following image; as the image itself is just of the central plane of the brain and some of these structures (ie, the amygdala, there is one on each side of the brain) are off-center, this schematic is not perfect, but it gives a rough approximation of the proximity of many of these structures.

Note: In some of the following sections where I discuss signaling between different centers I will include an image with arrows that demonstrate this signaling. Each arrow is colored according to the center it projects from (with the hypothalamus in black). This gets complex when there are lots of arrows, and the complexity increases as you go down the page as I add more arrows into the image. The main point is not to see and understand the specific details of all of the various signaling, but rather to appreciate the overall complexity and the fact that many different brain regions that perform various functions in the body also impact feeding behavior. Thus, other aspects of physiology distinct from feeding can influence these centers and indirectly impact feeding.

Nucleus tractus solitarius (“NTS”)

The NTS lies within the brainstem and receives several types of signals including gustatory sensation (it is the entry point to the brain for taste information from the oral cavity) as well as signals transmitted from the vagus nerve (discussed below), among others. The NTS projects to higher central nervous system structures that control both homeostatic and hedonic aspects of eating.

The NTS neurons have several receptors (ie, for leptin and GLP-1, both discussed later in this series), release several substances (GABA, norepinephrine, GLP-1, and CCK), and project to several places including the lateral parabrachial nucleus (“PBN”), the medulla, and portions of the hypothalamus, among others. POMC neurons are also present in the NTS. The neurons that release CCK (a satiety-promoting hormone) additionally project to both the paraventricular and arcuate nuclei of the hypothalamus (the “PVH” and “ARH”, respectively). The neurons that are sensitive to leptin project to the ventromedial nucleus of the hypothalamus (“VMH”) to increase leptin sensitivity. Collectively, these actions lead to a decrease in appetite.

The NTS has other functions as well; if glucose is low it will help activate a counterregulatory response that stimulates food intake. Cancer associated with anorexia leads to elevated levels of growth/differentiation factor 15 (“GDF-15”) and the receptor for this is expressed in the NTS as well as the area postrema (“AP”); ultimately the anorexia is mediated by the CGRP neurons in the PBN.

Thus, overall the NTS serves as a relay point and both processes and transmits many of the body’s signals to other brain structures.

Parabrachial nucleus (“PBN”)

The PBN is comprised of a small group of nuclei at the junction of the midbrain and the pons in the brainstem and generally balances internal signals reflecting a negative state against metabolic need. It receives gustatory input from the NTS (and thus is critical for taste aversion), information regarding discomfort from the NTS & spinal cord, inhibitory input related to hunger from the ARH and PVH, and connects with several brain centers to integrate numerous signals from the body into various brain networks. It processes a variety of aversive visceral signals such as pain, nausea, and fear. For example, the PBN Y₁ receptors are acted upon by NPY from the ARH when in a state of hunger to mask feelings of pain and thus promote food intake.

When not inhibited by AgRP input, the PBN can stop feeding via its calcitonin gene-related peptide (“CGRP”) neurons that project to the central amygdala (“CeA”); this will lead to meal-specific satiety but will not decrease total daily food intake. Thus, after consuming sufficient food and with decreased AgRP signalling, the PBN sends CGRP to the CeA which then sends further signals to the AP and NTS to provoke feelings of satiation. Satiety signals such as amylin and CCK (discussed later in this series) can activate PBN(CGRP).

When CGRP leads to satiation this usually comes with an aversive component (ie, nausea, or discomfort associated with fullness). The PBN can also inhibit feeding in a non-aversive fashion by utilizing glutamatergic neurons; these are stimulated by projections from the PVH.

Dorsal raphe nucleus (“DRN”)

The DRN has many serotonergic neurons, receives input from several brain areas (ie, the spinal column, brainstem, and ARH) and gives output to several different brain areas (ie, the ARH, NTS, and PVH). In general when CNS serotonin is decreased it leads to hyperphagia while when CNS serotonin is increased it leads to anorexia. The DRN generally releases serotonin but is inhibited by NPY inputs from the ARH. Serotonin signaling is discussed further below.

Ventral tegmental area (“VTA”) and nucleus accumbens (“NAc”)

The VTA and NAc help to integrate homeostatic and hedonic centers via connecting ARH(NPY) input to dopaminergic output. Dopaminergic signaling is discussed further below, but the “mesolimbic pathway” that comprises much of hedonic signaling consists of projections from the VTA to the NAc.

Central Amygdala (“CeA”)

The amygdala is part of the limbic system; it has roles in feeding, behaviors, memory, stress response, emotional states, and more. It contains at least 13 subnuclei; the CeA is one of the most important for feeding behaviors. As one example, stressful conditions can lead to decreased insulin levels, resulting in greater activation of NPY neurons (which have insulin receptors) in the CeA – this can help induce “stress eating”. The CeA receives input from many different brain areas and sends output to several different locations and thus plays a central role in linking fear, anxiety, stress, and the reward system to the regulation of feeding behavior. As further examples, it plays a role in increasing palatable food consumption with certain emotional states (ie, “eat your feelings”), and it can decrease the desire to eat when experiencing intense fear.

Note: The central amygdala has interactions with many centers so I will include the relevant arrows in an image at the end to demonstrate the complexity.

Bed nucleus of the stria terminalis (“BNST”)

The BNST interacts with several locations associated with reward as well as anxiety and works closely with the CeA. When activated by stressful situations (in part mediated by corticotropin-releasing factor acting on BNST receptors) it will generally inhibit food intake (at least in part via projections to AgRP neurons) and promote actions that more directly respond to the stressful situation.

Area Postrema (“AP”)

The AP has fenestrated capillaries and therefore is a circumventricular organ, meaning it is outside of the blood-brain barrier. It can thus detect various hormones and other components in the bloodstream, while also receiving signals from the NTS to further integrate sensory information. It can process and pass these signals to the medulla, which receives its own sensory nerve input, to help integrate various signals throughout the body. The AP has a subpopulation of neurons with receptors for appetite-reducing peptides that generates excitatory signals to the NTS or PBN, subsequently inhibiting food intake.

One example is the GDF-15 molecule mentioned above. It is secreted by a host of cells and tissues in response to various stressors (ie, cancer, heart failure, renal failure) and has receptors expressed in the AP and NTS. When binding to these receptors this leads to a sickness response of anorexia, nausea, and vomiting. Of interest, GDF-15 is also produced by the human placenta and may drive the nausea and emesis associated with hyperemesis gravidarum.

Lateral habenula (“LHb”)

The habenula is divided into medial and lateral components. The LHb acts as a central node that connects forebrain, midbrain, and hindbrain regions together, and it can influence both dopaminergic and serotonergic signaling. The LHb is generally thought to help modulate reactions to aversive tastes but when inhibited can also lead to increased consumption of palatable food. The exact inputs that help modulate feeding behavior have not yet been defined, though several potential inputs include the various centers discussed above.

Thalamus

The thalamus integrates sensory information and projects it to higher brain centers. The paraventricular thalamus (“PVT”) in particular receives input from many different regions of the brain, balances the urgency of different stressors (ie, danger, pain, low energy supply, glucose levels, etc), and projects outputs to many brain centers to motivate behaviors according to what is needed at that moment in time. The figure below demonstrates some of these various projections to and from the PVT.

Reproduced from: Petrovich GD. The Function of Paraventricular Thalamic Circuitry in Adaptive Control of Feeding Behavior. Front Behav Neurosci. 2021 Apr 27;15:671096. doi: 10.3389/fnbeh.2021.671096. PMID: 33986649; PMCID: PMC8110711.

Serotonin and Dopamine

While not specific brain regions, both serotonin and dopamine have pathways in the brain involving several of the previously mentioned sites that influence food intake in separate ways, thus I will discuss their roles in food intake regulation here.

Reproduced from: Campos A, Port JD, Acosta A. Integrative Hedonic and Homeostatic Food Intake Regulation by the Central Nervous System: Insights from Neuroimaging. Brain Sci. 2022 Mar 24;12(4):431. doi: 10.3390/brainsci12040431. PMID: 35447963; PMCID: PMC9032173.

Serotonin

Serotonin is a neurotransmitter that has several roles in human physiology. Regarding appetite, hunger, and related aspects of eating, it is primarily synthesized by neurons in the DRN of the midbrain though it is also secreted by enteroendocrine cells of the GI tract (the vagal sensory nerves can detect this serotonin and trigger peristalsis, which helps process food through the gut). Serotonergic neurons can project to many areas of the brain and influence mood, cognition, and energy expenditure in addition to eating. Serotonin levels gradually increase while eating and will generally inhibit eating when elevated as the serotonergic neurons project to the ARH to stimulate POMC neurons and inhibit AgRP/NPY neurons. NPY in turn can decrease serotonin release. When looking at specific serotonin receptors things become more complicated; activation of 1B receptors seems to decrease eating while activation of 1A receptors seems to stimulate greater eating.

Serotonergic neurons also project to the VTA to decrease intake of highly palatable foods when not hungry and thus can modulate hedonic aspects of food intake. While serotonin can help suppress palatable food consumption, both serotonin and dopamine can invoke reward responses that are subject to habituation with repetition; regarding eating this can lead to increased palatable food-seeking behavior to continually experience the reward. An example of this would be if you were to eat certain foods repeatedly because they taste good and then you end up developing cravings for them.

Dopamine

Dopamine is a separate neurotransmitter with several roles in human physiology. Dopaminergic signaling is influenced by ghrelin and leptin, and many brain regions take part in signaling with dopamine. The mesolimbic dopamine system incorporates signals from several sites discussed above such as the BNST, CeA, PBN, and the lateral hypothalamic area (discussed in the previous article in this series). The VTA in the midbrain can then send dopaminergic projections to the NAc and prefrontal cortex which collectively oversee aspects of food seeking and goal-directed behaviors.

Within the stratum dopamine D2 receptor availability is inversely correlated with obesity while ingestion of palatable foods and sugars increases dopamine release. Thus, as individuals with obesity have fewer receptors they will need to consume more of these foods to achieve the same total level of dopamine signaling. Additionally, as mentioned above, both serotonin and dopamine are subject to habituation with repetition, leading to more food seeking behaviors to continually experience the associated reward.

Therefore, dopamine is an essential signal for hedonic food intake regulation and dopamine signaling generates motivation for desirable foods. Additionally, NPY can enhance the release of dopamine, and thus when hungry this can generate even more favorable reactions to food items and make them seem more rewarding to consume.

Vagus nerve

The vagus nerve is technically a cranial nerve but innervates many organs in the body, receiving input from and providing output to several different targets, and ultimately bringing afferent input into the brainstem. This is shown in the schematic below.

Reproduced from: Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Peripheral signals from the GI tract act on afferent fibers of the vagus nerve and are relayed to the dorsal vagal complex in the medulla of the brainstem, which consists of the dorsal motor nucleus of the vagus nerve, the NTS, and the AP. Information from spinal sensory nerves, which also receive signals from various components of the GI system, additionally converges on the medulla and complements the vagal sensory nerves (ie, the spinal sensory nerves may preferentially detect glucose levels while the vagal sensory nerves may preferentially detect fat). These sensory nerves can express several different compounds including CART, CGRP, and other peptides to mediate downstream effects. Thus, the medulla, and primarily the NTS, is the entry point into the brain for the various signals that come from the GI system and can both process and then relay these signals to other brain centers.

Regarding the signals that the vagus nerve detects, besides various nutrients it will also detect the various gastrointestinal peptide hormones secreted by the enteroendocrine cells of the GI tract as well as neurotransmitters such as serotonin that these cells produce. The vagus nerve also has stretch receptors primarily in the stomach that detect gastric distension.

The vagus nerve is not just a sensory nerve; it can influence motor control of the GI tract with efferent fibers that alter the profile of GI tract secretions and motility as well as nutrient absorption, storage, and mobilization. Thus, the vagus nerve detects all of the local effects of food ingestion that occur in the GI tract, helps process these signals for higher brain centers, and then provides output to the GI tract to assist in processing of these nutrients.

Summary

Below I have included a diagram with all of the projections included above.

Thus, there are several brain regions beyond the hypothalamus that are relevant for both homeostatic and hedonic food intake considerations. Many, if not all of them, interact with the hypothalamus to some degree, helping to influence or carry out homeostatic energy regulation. Several of them participate in dopaminergic and serotonergic signaling, as well as interact with sensory input, collectively influencing hedonic motivations.

In the next lesson I will discuss aspects of hedonic eating in more detail and then provide a figure demonstrating the higher cortical conscious decision-making brain regions that influence hunger and appetite-guided choices.

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