Hypothalamic Influences of Homeostatic Hunger Regulation

Introduction

In the introduction to this series I provided a general overview of terminology, drawing a distinction between “hunger” (essentially a drive to consume food) and “appetite” (a desired for a specific food item that will provide a rewarding experience when consumed), as well as between “homeostatic” considerations (this regards energy balance, with hunger indicating the body needs to replenish energy stores) and “hedonic” considerations (this regards rewarding aspects of food intake, such as having increased appetite or cravings for specific food items). I then provided a general overview of some of the considerations for hunger and appetite regulation, mentioning that the hypothalamus is in a good position to survey signals from the rest of the body.

In many respects the hypothalamus is the key driver of homeostatic energy balance. I will discuss the most relevant aspects of the hypothalamus regarding food intake regulation in this article.

Overview of the hypothalamus

As shown in the last lesson, the hypothalamus is positioned in a central aspect of the brain, just above the brainstem.

The hypothalamus has several different sections (mostly referred to as nuclei) that help control many different behaviors and actions in the body, some of which pertain to energy regulation and food intake. The ones that seem to be most relevant for food consumption are the arcuate nucleus (“ARH”), the paraventricular nucleus (“PVH”), and the lateral hypothalamus (“LHA”). Other important hypothalamic centers for food intake regulation include the ventromedial (“VMH”) and dorsomedial (“DMH”) nuclei. I will discuss each of these centers in more detail here.

The following diagram shows the approximate locations of these various hypothalamic nuclei. It also shows that several of these nuclei abut the 3^rd ventricle, which itself is connected to the median eminence (“ME”). The ME has a fenestrated epithelium, meaning compounds in its blood supply are able to permeate the ME to enter the brain. Thus, the ME is one of the brain’s circumventricular organs, implying it allows a breakdown of the blood-brain barrier. This is controlled to some degree by tanycytes, a cell type that not only helps to regulate the function of the ME but also helps to transport the various hormones (ie, leptin and ghrelin) and other blood products (ie, glucose and amino acids) to the hypothalamus directly. Certain hypothalamic regions provide feedback to help regulate the function of the tanycytes. In this way the hypothalamus is able to directly sense various energy and food-related signals from the body.

Reproduced from: Elizondo-Vega R, Cortes-Campos C, Barahona MJ, Oyarce KA, Carril CA, García-Robles MA. The role of tanycytes in hypothalamic glucosensing. J Cell Mol Med. 2015 Jul;19(7):1471-82. doi: 10.1111/jcmm.12590. Epub 2015 Jun 17. PMID: 26081217; PMCID: PMC4511346.

Now I will discuss aspects of each of the more relevant hypothalamic nuclei in greater detail.

The arcuate nucleus of the hypothalamus (“ARH”)

The ARH seems to be the primary center in the brain that controls the homeostatic aspects of eating. It is in the mediobasal hypothalamus, just above the ME of the 3^rd ventricle, so as described above it is in an optimal position to survey the various peripheral signals that move throughout the bloodstream. There are multiple neuronal subpopulations in the ARH, with various modulating and at times opposing roles influencing eating behavior. The ARH receives input from and projects output to many different areas of the brain, both within and beyond the hypothalamus, as shown in the diagrams below (drawn with brain sections of a mouse). These projections influence homeostatic energy regulation as well as the hedonic aspects of eating.

ARH inputs

Reproduced from: Deem JD, Faber CL, Morton GJ. AgRP neurons: Regulators of feeding, energy expenditure, and behavior. FEBS J. 2022 Apr;289(8):2362-2381. doi: 10.1111/febs.16176. Epub 2021 Sep 13. PMID: 34469623; PMCID: PMC9040143.

ARH outputs

Much of the energy balance regulation stems from activity of the enzyme AMP-activated protein kinase (“AMPK”), which assesses overall energy status in several ways. It detects the ratio of AMP and ADP to ATP, all of which are cellular signals of current energy supply. It receives input from hormones that transmit energy balance signals from the rest of the body, such as ghrelin (a hunger-stimulating hormone that increases AMPK activity) and leptin (a hormone secreted by adipose tissue (body fat) reflecting long-term energy stores that decreases AMPK activity); these and other relevant hormones are discussed in greater detail later in this series. AMPK also detects other signals in the bloodstream such as glucose. After integrating these signals, AMPK influences the signaling of the various ARH neuronal subpopulations to influence overall hunger levels and associated behaviors.

I will describe the most relevant ARH neuronal subpopulations here.

Note: The enzyme mammalian target of rapamycin (“mTOR”) that helps govern protein synthesis has reciprocal activity to AMPK in peripheral cells. Therefore, the signals for growth that stimulate mTOR will likely be more active if the AMPK activity reflects a state of appropriate energy and amino acid availability. This is one reason it may be more difficult to build new muscle and retain current muscle when in a calorie deficit compared to maintenance or a calorie surplus, though more research is needed to directly test this hypothesis.

AgRP neurons of the ARH

The Agouti-related protein (“AgRP”) neurons are primarily orexigenic, meaning they generally increase food intake when active. They have other roles as well that make energy and fat storage more likely:

They can decrease sympathetic nervous system activity to inhibit thermogenesis and suppress unnecessary energy expenditure.
They can increase carbohydrate utilization while decreasing lipolysis (fat burning) and influence glucose homeostasis.
They project to the parabrachial nucleus (“PBN”) to suppress pain (making pain less likely to inhibit food consumption).
They can additionally promote an anxiolytic response which in animals will increase their willingness to explore potentially dangerous areas for food.
Through actions in the paraventricular thalamus the AgRP neurons promote attraction to food odors over other odors when hungry.

AgRP neurons project to many different areas within and outside of the hypothalamus in non-collateralizing fashion; this means that distinct subsets of these neurons can innervate separate brain areas to induce various specific effects. They subsequently secrete some combination of AgRP, neuropeptide Y (“NPY”), γ-aminobutyric acid (“GABA”), and potentially other neuropeptides.

AgRP is an inverse agonist of melanocortin receptor 4 (“MC4R”) in the paraventricular nucleus of the hypothalamus (“PVH”, discussed below) and prevents the action of α-melanocyte-stimulating hormone (“α-MSH” – this is produced by the POMC neurons discussed below). Thus, this counteracts the POMC neurons and this leads to increases in hunger.
NPY specifically has 5 Y-receptors (1, 2, 4, 5, and 6), with Y₄ densely expressed in the area postrema (“AP”) and Y_1,2,5 expressed throughout the central nervous system in areas involved in homeostatic and hedonic food intake regulation. Binding to Y₁ and Y₅ can directly increase hunger. NPY can induce anxiolytic effects and influence brain regions involved in stress such as the amygdala, locus coeruleus, and the hippocampus. This may increase one’s desire to eat highly palatable foods, and NPY’s role in the ventral tegmental area (“VTA”) and the nucleus accumbens (“NAc”) via the Y₁ receptor seems mostly hedonic. NPY additionally plays a role in substance use disorders with reward-inducing addiction properties and thus may mediate some of the aspects of “food addiction” (this is a controversial topic).
GABA can potentiate the effects of AgRP and NPY.

The following image demonstrates how these secretion products can act on the PVH, using a diagram of a mouse’s brain. The image shows that insulin and leptin stimulate POMC neurons and inhibit AgRP neurons while ghrelin stimulates AgRP neurons; these are all discussed in more detail later in this series.

There are several factors (discussed in more detail later) that can modulate the activity of AgRP neurons:

When ghrelin levels increase and leptin levels decrease (generally due to an energy deficit) both presynaptic and postsynaptic changes occur that increase the firing rate of AgRP neurons. AgRP neurons are additionally stimulated by decreases in glucose as well as cold exposure.
Alternatively, the enteroendocrine satiety signals of serotonin, CCK, and PYY can inhibit AgRP activity to promote satiety (the former two over a shorter time course than the latter). Insulin and leptin can both inhibit AgRP activity when elevated, leptin doing so directly and also via influencing the dorsomedial nucleus of the hypothalamus (“DMH”, discussed below) that sends input to the AgRP neurons.
The vagus nerve can also influence AgRP neurons, transmitting signals via intestinal chemosensation (ie, of the GI hormones) and mechanosensation (ie, of stomach distension) to the brain.

Regarding considerations for obesity:

It is hypothesized that AgRP neurons receive hedonic feedback leading to an upward shift in body weight and/or adiposity settling points, particularly when in an obesogenic environment, which will make the body naturally gravitate towards a higher weight.
Obesogenic diets seem to disrupt the normal basal activity patterns of AgRP neurons and at least in rodents high-fat diets can blunt the typical AgRP responsiveness to inhibitory modulators (ie, the GI satiety peptides discussed later in this series); these changes occur even prior to substantial weight gain and seem only partially reversible with weight loss.
Additionally, AgRP density & expression is negatively correlated with BMI; thus the hunger inducing effects are expected to increase with weight loss.

Note: After food presentation but before consumption the AgRP neurons rapidly decrease their firing frequency; thus they seem to perform a role in promoting homeostasis in an anticipatory manner in addition to responding to the energy balance signals they receive at any given point in time.

POMC/CART neurons

Pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (“POMC/CART”) neurons are primarily anorexigenic, meaning they decrease hunger and promote satiety. Their activation leads to the release of several products that result from various post-translational modifications, as seen in the following figure. Importantly, this ultimately results in the potential production of multiple melanocyte stimulating hormone (“MSH”, also referred to as melanocortin) compounds, such as α-MSH and β-MSH.

Reproduced from: Moscowitz AE, Asif H, Lindenmaier LB, Calzadilla A, Zhang C, Mirsaeidi M. The Importance of Melanocortin Receptors and Their Agonists in Pulmonary Disease. Front Med (Lausanne). 2019 Jun 27;6:145. doi: 10.3389/fmed.2019.00145. PMID: 31316990; PMCID: PMC6610340.

α-MSH functions in the PVH, where it activates MC3R and MC4R to decrease food intake. Overall, these MSHs inhibit AgRP production. Various subpopulations of POMC neurons may additionally express GABA or glutamate. CART specifically is a neuropeptide with many physiologic functions including feeding regulation; more research is needed to fully clarify its role in feeding and other behaviors. For this reason I will not discuss it further.

As mentioned above, AgRP neurons can inhibit the action of POMC neurons. These POMC neurons are stimulated by leptin and insulin and they also receive input from cholinergic neurons in the DMH; in general they are activated by an energy surplus. They also can rapidly alter activity in response to sensory food perception, serotonin, CCK, and PYY. Similar to the AgRP neurons, the presentation of food cues can activate POMC neurons so there is likely a role of POMC in the anticipation of satiety. The POMC neurons will function to induce satiety, alter liver physiology to a postprandial state (mediated by melanocortin-dependent control of sympathetic nervous system activity), and increase energy expenditure.

Note: Cannabinoids (which are naturally produced to a degree in the body but also generated with marijuana use) can stimulate a switch from α-MSH to β-endorphin release from POMC; this can stimulate an increased desire for food intake.

Regarding considerations for obesity:

In rodents a prolonged high-fat diet can lead to altered mitochondrial dynamics and cellular interactions resulting in impaired calcium handling and inhibition of POMC neuron firing. This will lead to decreased satiety/satiation and thus increased food intake.
MC4R mutations are the most common cause of monogenic forms of obesity, and as mentioned above this is the primary hunger-related receptor that POMC neurons act upon. It can be worth considering testing for this or other genetic causes of obesity in individuals who develop obesity at a young age and seem to engage in considerably greater eating and food-seeking behaviors than their peers.

The following figure provides a diagram of the AgRP & POMC neurons in the ARH receiving various inputs and then projecting outputs that influence hunger. You can see how NPY from the AgRP neurons can inhibit the POMC neurons:

Reproduced from: Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, Ryan DH, Still CD; Endocrine Society. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015 Feb;100(2):342-62. doi: 10.1210/jc.2014-3415. Epub 2015 Jan 15. Erratum in: J Clin Endocrinol Metab. 2015 May;100(5):2135-6. PMID: 25590212.

Other pertinent ARH cell types

While the AgRP and POMC neurons are the best described and most frequently discussed ARH neuronal subpopulations, there are others that also have roles in eating and energy regulation.

Tyrosine hydroxylase (TH) neurons:

These neurons release dopamine and GABA, and are generally orexigenic. They are stimulated by increases in ghrelin, which leads to an increase in the TH neuron firing rate. They stimulate the AgRP neurons (via the D1-like receptor) while they inhibit the POMC neurons (via the D2-like receptor). They can additionally inhibit the PVH (which drives greater food intake) and they may also help control the function of the ME (discussed above).

Oxytocin-receptor expressing glutamatergic neurons (OXTR-Vglut2):

These neurons rapidly promote satiety via synergistic effects with POMC neurons on post-synaptic MC4R-expressing neurons in the PVH.

Prepronociceptin (PNOC)-expressing neurons:

These neurons are GABAergic (meaning they secrete GABA) and in rodents are activated by short-term high-fat diet feeding. They directly inhibit POMC neurons and stimulate projections to the bed nucleus of the striae terminalis to increase food intake.

Nonneuronal cell types:

There is some evidence that other cell types also play a role in energy balance in the ARH. One example is astrocytes, which can modulate glucose uptake into the brain and influence insulin and leptin signaling to regulate feeding.

The paraventricular nucleus of the hypothalamus (“PVH”)

The PVH receives significant input from the AgRP & POMC neurons of the ARH and acts as a downstream effector of the ARH. AgRP neuronal output inhibits the PVH; when AgRP signaling is not present the PVH will typically send glutamatergic signals to the PBN and elsewhere to promote satiety. The PVH additionally incorporates information from neuroendocrine and autonomic nervous system functions to integrate emotional and stress responses and ultimately influence motivated behaviors. It sends projections back to the ARH (particularly to the AgRP neurons), to other areas of the hypothalamus and brain (such as the pituitary and the nucleus tractus solitarius), as well as to the spinal cord. It additionally exerts control over metabolism via releasing thyrotropin-releasing hormone and corticotropin-releasing hormone.

The diagram below shows how the PVH takes signals from the ARH and coordinates with other brain areas such as the PBN to promote satiety:

Reproduced from: Jais A, Brüning JC. Arcuate Nucleus-Dependent Regulation of Metabolism-Pathways to Obesity and Diabetes Mellitus. Endocr Rev. 2022 Mar 9;43(2):314-328. doi: 10.1210/endrev/bnab025. PMID: 34490882; PMCID: PMC8905335.

The lateral hypothalamus area (“LHA”)

The LHA is intimately involved in eating behaviors and overall is quite complex. It helps to drive food consumption that is rewarding in value while influencing aversion to undesirable tastes. Thus, the LHA modulates the hedonic aspects of taste preferences. It also incorporates homeostatic considerations as it receives input from AgRP and POMC neurons from the ARH. Consequently, the LHA links homeostatic and hedonic aspects of eating by connecting the homeostatic energy regulation mechanisms of the ARH to the mesolimbic dopamine circuitry (discussed later in this series) that collectively helps provide reward learning aspects of food consumption. This not only drives the desire for consumption of more palatable foods but also leads to greater preferences for them with repeat exposures. Similarly, the LHA helps to ingrain learned negative responses to aversive food tastes.

The LHA has several different neuronal subpopulations, and each can potentially contribute to several functions as shown by the orexin subpopulation in the following figure:

Reproduced from: Fakhoury M, Salman I, Najjar W, Merhej G, Lawand N. The Lateral Hypothalamus: An Uncharted Territory for Processing Peripheral Neurogenic Inflammation. Front Neurosci. 2020 Feb 12;14:101. doi: 10.3389/fnins.2020.00101. PMID: 32116534; PMCID: PMC7029733.

The LHA neuronal subpopulation that expresses orexin (also called “hypocretin”) works with a separate subpopulation that expresses melanin concentrating hormone (“MCH”). The former neurons are activated by fasting and low glucose levels, with influences from ghrelin and leptin, and are rapidly inactivated by food intake; when active they seem to project to the VTA and contribute to hedonic aspects of eating. The MCH-expressing neurons project to the NAc which is an integral component of the reward system. Both of these subpopulations inhibit POMC neurons when active. They also project to the medulla in the brain stem as well as the spinal cord and aid in the regulation of salivation, gastric motility, and pancreatic hormone secretion.

It has classically been described that if the LHA is destroyed this will induce hypophagia and starvation. However, it is now known this feature was due to local destruction of dopamine projections from other brain centers that pass through the LHA. Rather, some LHA neuronal subpopulations favor greater food intake while some favor decreased food intake. LHA GABAergic neurons (“LHA(GABA)”) seem to functionally oppose the glutamatergic (“LHA(GLUT)”) neurons in this regard. When the LHA(GABA) neurons are activated these enhance motivation for food consumption as well as the rewarding aspects of food intake, but when the LHA(GLUT) neurons are activated these project to the lateral habenula and induce satiety. These glutamatergic neurons receive inhibitory input from AgRP neurons to help prevent satiety, to enhance sweet taste sensations, and to decrease aversive taste sensations when hungry.

Thus, the LHA has several different neuronal subpopulations that connect to many different brain areas and coordinate various aspects of emotional states and behavioral processes, including feeding behavior. Importantly, the LHA links the homeostatic and hedonic aspects of food consumption.

The ventromedial nucleus of the hypothalamus (“VMH”)

The VMH does not seem to directly influence food consumption, but it does monitor energy status and adiposity via glucose and leptin signaling, and it has receptors for other relevant hunger-related hormones such as ghrelin. The VMH takes these inputs and then helps modulate various behaviors, even if these behaviors are not directly related to eating. For example:

The VMH may detect a decrease in your glucose level if you become hypoglycemic for whatever reason.
The VMH may then help provoke an increase in sympathetic nervous system activity as well as glucagon release to maintain your blood glucose concentration at an adequate level.
As a consequence of these glucose-maintaining counterregulatory mechanisms you may sense a need to eat food.

Thus, the VMH helps to stimulate sensations (such as anxiety) that lead to behaviors needed to maintain an adequate energy balance, and these behaviors may include food seeking and consumption.

The dorsomedial nucleus of the hypothalamus (“DMH”)

The DMH helps control energy expenditure while also providing feedback to the ARH:

There are MC4R receptors in the DMH that help regulate adaptive thermogenesis (a decrease in energy expenditure experienced when in a calorie deficit). Leptin has a role in the DMH that seems related to thermogenesis and energy expenditure as a whole. These influences on energy expenditure are likely mediated by projections that alter sympathetic nervous system activity.
GABAergic neurons in the DMH responsive to leptin project to the ARH and lead to both stimulation of POMC neurons and inhibition of AgRP neurons while also influencing circadian control of food intake.

Thus, the DMH helps to maintain energy balance by impacting the energy expenditure side of the equation while also providing feedback to the centers more involved in hunger regulation. This is one example of how energy intake and energy expenditure are linked.

The below image demonstrates the complexity of interactions between the various hypothalamic centers regarding feeding control while also showing a small amount of neural input. This image does not demonstrate the full complexity of various neuronal subpopulations, other inputs into the hypothalamic nuclei, or output to other brain regions, but even disregarding all of that the complexity is still obviously quite high.

Reproduced from the textbook Neuroscience Online

Summary

The hypothalamus has several nuclei that contribute to energy regulation and general homeostasis within the body. These nuclei process physiologic peripheral inputs as well as influences from other brain regions to help generate underlying motivational aspects that drive our behaviors. Regarding feeding, the ARH interprets underlying energy balance signals to help promote feelings of hunger or satiety, with influences from the LHA, DMH, and other centers as well, and then projects output to the PVH and elsewhere. The PVH incorporates these signals and signals from other neurologic centers and then sends output to other brain regions such as the PBN.

In this way, all of these hypothalamic centers contribute to a complex network that weighs the importance of many different physiologic functions against each other, promoting increased hunger when needed for homeostatic considerations. Now that I have discussed the hypothalamus In the next article I will discuss some of the non-hypothalamic intermediary brain regions that influence hunger and appetite, many of which interact with the hypothalamus and/or contribute to hedonic eating considerations.

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