Hypothalamic Regulation of Appetite

Katherine A. Simpson; Niamh M. Martin; Steve R. Bloom


Expert Rev Endocrinol Metab. 2008;3(5):577-592. 

In This Article

Hypothalamic Regions Important in Appetite Regulation

The ARC is a key hypothalamic nucleus in the regulation of appetite. In mice, lesions of the ARC using monosodium glutamate produce obesity and hyperphagia.[12] Anatomically related to the median eminence, the ARC is not fully insulated from the circulation by the blood-brain barrier and, hence, is strategically positioned to integrate a number of peripheral signals controlling food intake (Figure 2).[13,14] Two major neuronal populations in the ARC are prominently implicated in the regulation of feeding. One population, localized more medially in the ARC,[15] increases food intake and coexpresses neuropeptide Y (NPY) and Agouti-related protein (AgRP). The second population of neurons, coexpressing cocaine- and amphetamine-related transcript (CART) and pro-opiomelanocortin (POMC), inhibits food intake and tends to cluster more laterally in the ARC.[16] Neuronal projections from these two populations then communicate with other hypothalamic areas involved in appetite regulation, such as the PVN, DMN and LHA.[17,18,19,20] This network of neuronal circuitry can be modulated by peripheral signals, such as leptin and insulin.

The main hypothalamic nuclei, neuropeptides and pathways involved in the regulation of appetite. Circulating hormones act on the ARC, which has an incomplete blood-brain barrier and, hence, can affect downstream pathways, which modulate appetite control. In the ARC, orexigenic neurons coexpress NPY and AgRP, whereas neurons coexpressing POMC and CART are anorexigenic. In the ARC, activation of AMPK leads to increased food intake, an effect that is inhibited by insulin and leptin. AgRP = Agouti-related protein; AMPK = Adenosine monophosphate protein kinase; ARC = Arcuate nucleus; CART = Cocaine- and amphetamine-related transcript; CB1 = Endocannabinoid receptor 1; CCK = Cholecystokinin; DMN = Dorsomedial nucleus; GLP = Glucagon-like peptide; LHA = Lateral hypothalamic area; MCH = Melanin-concentrating hormone; NPY = Neuropeptide Y; OXM = Oxyntomodulin; POMC = Pro-opiomelanocortin; PYY = Peptide YY; PVN = Paraventricular nucleus; VMN = Ventromedial nucleus.

Cleavage of POMC by prohormone convertases PC1 and PC2 produces melanocortins, which exert their effects through binding to G-protein-coupled melanocortin receptors (MC-Rs). Five MC-Rs have been cloned, with differing affinities for POMC products.[21] Only MC3-R and MC4-R are expressed in the brain.[22] MC4-R is highly expressed in the hypothalamus, most notably in the PVN.[23] Targeted deletion of the MC4-R in mice results in hyperphagia and obesity, underlying the importance of this receptor in appetite regulation.[24] The role of the MC3-R remains less clear, but a putative role for this receptor as an autoreceptor in the feedback regulation of melanocortin circuitry in the brain has been postulated.[25,26,27] Supporting a role in the regulation of energy homeostasis, MC3-R-knockout mice have a higher fat content and reduced lean body mass.[28] Melanocortin peptides, including α-melanocyte-stimulating hormone (MSH), released from ARC POMC neurons, bind to downstream MC4-Rs to inhibit food intake.[29,30] Consistent with this, knockout mice lacking all POMC-derived peptides display increased food intake and weight gain.[31] AgRP is the endogenous antagonist for MC3-R and MC4-R.[32] While intracerebroventricular (ICV) administration of α-MSH to rats reduces food intake, this effect is inhibited by the simultaneous ICV administration of AgRP.[33] Furthermore, overexpression of AgRP recapitulates many features of MC4-R-deficient mice, including hyperphagia and obesity.[32,34] Such evidence suggests that melanocortinergic neurons may exert a 'tonic' inhibition on feeding, which is relaxed following AgRP antagonism of MC3-R and MC4-R, resulting in stimulation of feeding.

Several recent studies have demonstrated the importance of the melanocortin system in regulating energy homeostasis in humans.[35,36,37,38,39,40,41,42] MC4-R mutations account for approximately 6% of severe early-onset human obesity and as many as 90 different mutations have been associated with obesity.[35] Homozygous mutations in the POMC gene in humans results in early-onset obesity, adrenal insufficiency and red hair pigmentation.[37] In addition, Loos etal. found that common variants near the MC4-R gene influenced fat mass, weight and obesity risk.[43] The role of the MC3-R and β-MSH in obesity in humans is less clear, however mutation of the receptor and disturbed binding of β-MSH has also been implicated in individuals with morbid obesity.[38,44]

CART cDNA was originally isolated from rat brain using PCR differential display and its expression is regulated by acute administration of cocaine or amphetamine.[45] Nearly 3years after its discovery, CART was reported as a hypothalamic satiety factor.[46] CART mRNA expression is widespread in the CNS.[47] The majority of CART neurons in the ARC also contain POMC mRNA [48]. Animal studies have shown that ICV administration of CART inhibits food intake,[46] whereas ICV injection of CART antiserum increases food intake,[46,49] suggesting that CART peptide is an endogenous inhibitor of feeding. Preventing cerebrospinal fluid (CSF) flow between the third and fourth ventricles by plugging the cerebral aqueduct abolishes the anorectic effect of CART following its administration into the third ventricle.[50] This has led to the proposal that the anorectic effects of CART occur through the hindbrain rather than the hypothalamus.

Interestingly, in contrast to transgenic mouse models exploiting abnormalities in the melanocortin system, CART-deficient mice do not demonstrate significant alterations in feeding behavior or bodyweight when fed a normal diet.[51,52] However, a heterogenous CART missense mutation, which replaces Leu-34 with a phenylalanine residue, cosegregates with severe obesity through three generations of a human family.[53] Recent studies have proposed that CART may have an orexigenic role at other hypothalamic sites. Interestingly, CART injected directly into the VMN or ARC of fasted rats causes a significant increase in food intake at 1-2 h.[54] Similarly, twice daily intra-ARC injection of CART for 1week in rats results in a 60% increase in food intake, and CART overexpression using a CART transgene construct increases cumulative food intake and weight gain.[55] This suggests that there may be distinct neuronal circuits within the hypothalamus in which CART can act as an orexigenic or anorexigenic signal.

Within the hypothalamus, NPY has been implicated as an important physiological regulator of bodyweight through its effects on food intake and energy expenditure.[56] The majority of neurons expressing NPY in the hypothalamus are found within the ARC and over 95% of NPY neurons in the ARC coexpress AgRP.[25,57] NPY/AgRP neurons have extensive projections within the hypothalamus, including the PVN, DMN and LHA, which appear to be the main targets for the orexigenic effects of NPY.[25,57,58,59,60,61] ICV injection of NPY potently stimulates food intake in rats.[62] Repeated daily injections of NPY results in chronic hyperphagia and increased weight gain.[63] Both NPY content and release within the hypothalamus increase during the dark phase, when rats naturally feed.[64,65] In rodents, NPY mRNA in the ARC increases with food restriction and prolonged deprivation.[66,67] NPY acts at five different receptors (Y1-5 receptors), although NPY exerts its orexigenic effect predominantly via the Y1 and Y5 receptors.[68]

Approximately 20% of ARC NPY neurons innervate the PVN and DMN.[58,59] Stimulation of this pathway leads to increased food intake through direct stimulation of Y1 and Y5 receptors in addition to AgRP antagonism of MC3-Rs and MC4-Rs in the PVN.[69] Furthermore, local release of NPY within the ARC inhibits POMC neurons.[70] It is also postulated that NPY pathways are actively involved in the regulation of noradrenergic and serotonergic regulation of appetite.[69] In support of the critical role of the NPY/AgRP system in energy balance, ablation of NPY/AgRP neurons in adult mice reduces food intake and bodyweight.[71,72,73,74]

The PVN lies to either side of the roof of the third ventricle and it is thought to play a major role in the control of both appetite and endocrine function. The PVN is particularly important in the detection and integration of NPY, AgRP and melanocortin signals.[75] Microinjection of almost all known orexigenic peptides into the PVN, including NPY and AgRP, stimulate feeding.[76,77] NPY/AgRP and POMC neurons from the ARC communicate with PVN neurons containing corticotrophin-releasing hormone (CRH) and thyrotrophin-releasing hormone (TRH).[78,79] Both CRH and TRH have been implicated in the control of energy balance, by contributions to both food intake and energy expenditure.[80,81] Therefore, in energy balance, a key role for the PVN is to convey information from the ARC to other brain areas involved in appetite regulation.

The LHA is another key downstream target of neuronal projections from the ARC and contains the orexigenic neuropeptides melanin-concentrating hormone (MCH) and orexins. NPY, AgRP and α-MSH immunoreactive terminals are extensive in the LHA and are in contact with MCH and orexin-expressing cells.[82,83] MCH immunoreactive fibers project to the cortex and spinal cord, consistent with a potential role in appetite control and energy expenditure.[84,85] Interestingly, work by another group found that a subpopulation of MCH neurons express CART[86] and mainly project to the brainstem.[87] By contrast, MCH fibers lacking CART have been found to project to the forebrain, suggesting MCH may modulate food intake and energy expenditure through two separate neuronal projections depending on the presence of CART.[87] Lesioning of the LHA reduces bodyweight.[88,89,90,91] The severity of the LHA syndrome and near-normal recovery of food intake and bodyweight depends on the location and size of the lesion.[92] These observations led to the conception that the LHA was a 'feeding center' under restraint by signals from the VMN.[88]

To date, two MCH receptors have been cloned in humans, MCHR1 and MCHR2.[93,94] In rodents, however, only MCHR1 has been identified.[95,96,97] MCHR1-knockout mice and MCH-null mice have increased energy expenditure, locomotor activity and are resistant to diet-induced obesity.[98,99] By contrast, injection of MCH into the lateral ventricle of rats increases food intake, and fasting increases the expression of MCH mRNA.[100] Furthermore, transgenic mice overexpressing MCH are obese.[101] Interestingly, MCH has been implicated in increasing rapid-eye movement (REM) and slow-wave sleep,[102] suggesting that the role of MCH in modulating energy expenditure and food intake is done so through disruption of the sleep-wake cycle.

Orexin A and B act via two receptors, OX1R and OX2R.[103] ICV administration of these peptides increases food intake.[103] However, subsequent studies proposed that this may reflect associated heightened arousal and reduced sleep.[104]

Destruction of the DMN results in hyperphagia and obesity, though less dramatically than VMN lesioning.[91] The DMN contains a high level of NPY terminals[58,105,106] and α-MSH terminals originating in the ARC.[107] α-MSH fibers also project from the DMN to the PVN, terminating on TRH-containing neurons.[108] In the DMN, α-MSH fibers are in close apposition to NPY neurons.[109] α-MSH may suppress NPY gene expression in the DMN indirectly via separate inhibitory interneurons, possibly through GABAergic pathways.[109] It is proposed that decreased POMC input from the ARC to the DMN causes a reduction in MC4-R signaling, leading to decreased GABAergic inhibition of DMN NPY neurons and, hence, increased NPY mRNA expression. In diet-induced obesity,[110] obese Agouti mice and MC4-R-knockout mice,[111] NPY mRNA expression is increased in the DMN, whereas it is reduced in the ARC. This difference in NPY response is again highlighted by the finding that NPY levels in the DMN, in contrast to the ARC and PVN, are not elevated during fasting.[67] It is thought that lack of leptin signaling on NPY neurons in the DMN may partly account for this since leptin-deficient ob/ob mice show increased NPY mRNA in the ARC but not in the DMN.[111]

Recent work has focused on the role of cholecystokinin (CCK) in modulating NPY signaling and hence food intake.[112] Immunohistochemical studies have revealed that CCK-1 receptors and NPY are colocalized in DMN neurons and administration of CCK into the DMN downregulates NPY gene expression and inhibits food intake in rats.[113] Furthermore, Otsuka Long Evans Tokushima Fatty (OLETF) rats are a CCK-1-knockout model, and studies of these rats demonstrate hyperphagia and increased NPY mRNA expression in the DMN.[114] These findings suggest that neuropeptides, such as NPY, may have different effects on appetite regulation depending on which pathways they are acting on in the brain.

Lesions of the VMN result in rapid-onset hyperphagia and obesity,[88] leading to the hypothesis that the VMN is a satiety center, acting as a restraint on feeding. Consistent with this, neuroimaging studies in humans have shown increased signaling in the area of the VMN following an oral glucose load.[115] The VMN has a large population of glucoresponsive neurons that respond to blood glucose levels and numerous histamine, dopamine, serotonin and GABA neurons that respond to feeding-related stimuli.[116] The VMN receives NPY, AgRP and POMC neuronal projections from the ARC. Brain-derived neurotrophic factor (BDNF) is highly expressed in the VMN and is important during development for neuronal survival. It is a member of the neurotrophin family, which binds to the TrkB receptor, a human mutation of which has been described, resulting in severe obesity.[117] Lateral ventricle administration of BDNF reduces food intake and bodyweight.[118] Recent work implicates the role of ARC POMC neurons in activating VMN BDNF neurons to decrease food intake.[119,120] The VMN has also recently been described as the site of a novel hypothalamic appetite-regulatory circuit involving triiodothyronine (T3). Administration of T3 peripherally increases food intake in rats, without altering energy expenditure, and activates neurons in the VMN.[121] T3 in the brain is mainly produced by the deiodination of thyroxine to T3 by type 2 deiodinase (D2). Injection of T3 into the VMN also stimulates food intake and it has been proposed that intrahypothalamic production of T3 by D2 may modulate appetite.[121]


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