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Hypothalamic Mechanisms Contributing to Cancer Cachexia

Submitted:

19 November 2024

Posted:

20 November 2024

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Abstract

Cachexia is a complex multiorgan syndrome associated with various chronic diseases, characterized by anorexia and increased tissue wasting in the context of chronic inflammation. A specific form of this syndrome, known as cancer cachexia (CC), occurs alongside different types of tumors. The pathogenesis of CC is multifactorial, with inflammatory mediators and hormones released by either the tumor or the host identified as key drivers of the peripheral catabolic process through several direct mechanisms. Accumulating evidence indicates that the central nervous system (CNS) is also recognized as an integral component in the pathogenesis of CC. Hypothalamus has emerged as a critical brain area that senses and amplifies peripheral stimuli, generating an inappropriate neuronal signaling, leading to deregulation of feeding behavior and impaired control of energy homeostasis. Circulating cytokines may act in concert with hormones and neurotransmitters and perturbate the hypothalamic melanocortin system, shifting its activity towards the anorexigenic pathway and increase energy expenditure. The purpose of this review is to provide insights on the potential mechanisms mediating the hypothalamic inflammation in the context of anorexia and cachexia associated with cancer.

Keywords: 
Cancer cachexia
;  
anorexia
;  
hypothalamus
;  
cytokines
;  
neurotransmitters
;  
neuroendocrine
Subject: 
Medicine and Pharmacology  -   Other

Introduction

Cachexia is a serious clinical condition associated with several illnesses including chronic kidney disease, cardiac failure, chronic obstructive pulmonary disease and cancer [1,2]. Cancer cachexia (CC) occurs in almost 80% of patients with advanced cancer and it is directly correlated with impaired quality of life and short survival [3]. The principal cachexia features include loss of appetite, inflammation, insulin resistance and skeletal muscle wasting, with or without fat mass loss [4]. The pathogenesis of this syndrome is complex and is gradually being unraveled. Inflammatory mediators and tumor derived factors have been proposed as direct triggers of the catabolic process in skeletal muscle and adipose tissue. Even though muscle and fat loss remain the principal features of CC, there is growing evidence that organs such as liver, heart and gut are also affected by cachexia factors.
The brain mediates several metabolic and behavioral aspects associated with CC by sensing and amplifying peripheral inflammatory signals and altering the pattern of neurotransmitters and neuropeptides involved in feeding. The hypothalamus is an important structure for appetite regulation and body energy expenditure and may play a crucial role in CC development. The mediobasal hypothalamus (MBH), which contains the ventromedial arcuate nucleus (ARC) and the media eminence (ME) complex, is a key region that lacks the blood brain barrier (BBB) and functions as a ‘brain window’ for sensing circulating inflammatory molecules and hormones [5]. In the ARC resides the melanocortin system (MCS), a critical neural system comprised of neurons with opposite effect on the control of appetite and the homeostatic feedback regulation of energy balance [6]. Upon peripheral stimuli, the MCS may respond inappropriately and disrupt the balance between orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) pathways, leading to anorexia and hypercatabolic state [7]. In addition, it is known that hypothalamus is an important site for autonomic and endocrine homeostasis. Heightened sympathetic tone and aberrant neuroendocrine function have been observed in experimental cachexia models and are recognized as critical determinants of cancer associated tissue loss and increased energy wasting [8,9,10,11,12]. The paraventricular nucleus (PVN), specifically the parvocellular division, serves a crucial role in this process since it is able to integrate neuronal signals from hypothalamic nuclei and brainstem centers involved in appetite regulation (i.e., nucleus tractus solitarii-NTS and dorsal motor nucleus of the vagus-DMNV) and either generate a coordinated sympathetic output through projections to preganglionic neurons in the spinal cord [13] or secrete hypophysiotropic factors into the neurohemal zone of the median eminence modulating the neuroendocrine response [14].
The purpose of this review is to give information about cachexia mediators and neural pathways involved in central nervous system (CNS) dysfunction in the setting of cancer. The interplay between inflammatory molecules and neuronal groups will be discussed and how neuropeptides and neurohormones are affected to alter energy homeostasis and food intake. Although the process is complicated and involves multiple brain centers, this study will focus on the contribution of the hypothalamic mechanisms in driving this pathologic condition. Sheding light on the underlying pathophysiological pathways could help us identify novel molecular targets and expand the therapeutic options for cancer-related anorexia.

Cytokines Signaling in the Brain

Elevated circulating levels of pro-inflammatory cytokines have been reported in patients suffering from CC and have been associated with poor treatment outcomes [15,16,17,18,19,20]. These molecules have been shown to act on peripheral tissues stimulating catabolism and centrally affecting the mechanisms that regulate energy homeostasis [Figure 1]. Cytokines directly access the brain through the ME, where the BBB is incomplete, and reach the ARC. In addition, upon binding to their relative receptors on the BBB endothelial and glial cells can stimulate the synthesis of other chemical mediators such as prostaglandin-E2 (PGE2) and nitric oxide (NO) [21]. Finally, cytokines may communicate peripheral signals to brainstem centers via the vagal sensory terminals and ultimately to the hypothalamus [Figure 1] [22].
High cytokine levels have been detected in the hypothalami of tumor-bearing animals and associated with worsening of cancer associated anorexia [23,24,25,26,27,28,29,30]. Pharmacological activation of neuronal adenosine 5’-monophosphate-activated protein kinase (AMPK), a key component molecule involved in the regulation of energy homeostasis, was accompanied by the reduction of the hypothalamic levels of these cytokines, reversed anorexia and prolonged life span in animals [24].
Interleukin-1 (IL-1) is the prototype of the family of cytokines and in the brain plays a pivotal role in the organization of the hypothalamic cytokine network in response to systemic inflammatory challenges [31]. Under acute or chronic inflammatory stimuli the hypothalamic activity of IL-1β increases and correlates with the suppression of appetite [23,26,27,28,29,30,31,32]. In anorectic cancer animal models increased concentration of IL-1 in the cerebrospinal fluid (CSF) correlated inversely with food intake [33]. IL-1 interferes with the activity of the MCS as reported by studies using central administration of IL-1β and animal models of CC [34,35]. Selective treatment with intra-VMH injection of molecules that antagonize the IL-1 activity reduced the severity of cachexia [36].
Tumor-necrosis-factor-α (TNF-α) is another cytokine implicated in the induction of cachexia in acute and chronic diseases [37]. Rodents that received TNF-α both centrally and peripherally exhibited decrease in nutritional intake and wasting of body mass [38,39]. Its anorectic properties may be attributed to its suppressive action on chemosensitive neurons in the lateral hypothalamic area (LHA) and appetite regulating neurons in the ARC [40,41]. Moreover, increased hypothalamic TNF-α signaling has been shown to induce thermogenesis in the brown adipose tissue (BAT) mediated by an increase in β-adrenergic tone and rise of total body oxygen consumption, typical features of chronic cachectic states [42]. In experimental cancer models the use of recombinant human soluble TNF-α receptor or anti-TNF-α monoclonal antibodies improved food intake, body weight and increased survival [39,42].
The IL-6 family of cytokines is a group of cytokines that use the glycoprotein 130 (gp130) as the common signaling transducing component of the functional receptor complexes [43]. Among all the members of the IL-6 family, IL-6 and leukemia inhibitory factor (LIF) are considered to play a crucial role in the pathogenesis of anorexia and wasting syndrome in cancer. These molecules signal through activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which is the same pathway induced by leptin [43]. IL-6 is produced by both immune and tumor cells [44]. IL-6 plays a prominent role in the anorexia of infection and increased brain production has been associated with the development of LPS induced sickness behavior [45]. Central delivery or overexpression of IL-6 in the CNS, dampened feeding and increased energy expenditure and tissue wasting [46,47,48]. It is likely that IL-6 exerts its modulatory effects on metabolism by acting at the hypothalamus and affecting the expression of neuropeptides implicated in the control of energy balance [46,47,49]. Increased IL-6 signaling in the VMH induced fatty acid oxidation in the skeletal muscle through stimulation of the α-adrenergic pathway [50]. LIF is a pleiotropic cytokine with paradoxically opposite effects on different cell types [44]. LIF is produced by multiple cancer cell lines and fosters tumor development, metastasis and peripheral tissue wasting [51,52,53,54,55,56,57]. LIF can reach the brain parenchyma from the blood by crossing the BBB [58] where interacts at the hypothalamic level with the appetite regulating neuropeptides and interferes also with leptin secretion promoting hypophagia [52,57,59,60]. LIF can induce a sustained inflammatory reaction and a long-term anorectic response, in contrast with IL-1 and TNF-α, whose anorectic effect is attenuated after continuous administration [37]. In animals implanted with cancer cells LIF expression correlated with early onset and greater severity of anorexia-cachexia [60]. It has been demonstrated that LIF associated cachexia occurs independently of IL-6 because rLIF administration in wild type (WT) mice lacking IL-6 provoked anorexia and weight loss [51].

Hypothalamic Inflammation

Previous experiments demonstrated that peripheral administration of immune challenges and cytokines increased c-fos expression (marker of neural activity) in critical brain areas involved in feeding and metabolism, like the MBH and PVN [61,62,63]. In these centers high density of cytokine receptors is observed, implying that cytokines target these hypothalamic centers to mediate anorexia and metabolic changes [64,65,66]. Cytokines can act in the brain through paracrine interactions inducing further their local production, independently of their concentration in plasma, thus maintaining and amplifying locally the inflammatory signaling [44,67]. In the hypothalamus an important source of cytokines seems to be the activated microglia [68]. Infectious agents have been shown to stimulate cytokine production by microglia, which in turn affect the appetite regulating neuronal networks via NF-κB signaling [27,69,70,71]. In tumor bearing animals CD11b-positive hypothalamic microglia showed high expression of m-RNA levels of IL-1β, IL-6 and TNF-α in the early stages of the disease and before the appearance of cachexia symptoms [12]. Neurons whose cell bodies are mainly located in the periventricular hypothalamic area are also able to synthesize and release cytokines [72,73,74]. Inflamed endothelial cells further contribute to the amplification of the inflammatory state by increasing the expression of genes involved in cell adhesion, cytokine signaling and extracellular matrix (ECM) remodelling, leading to altered permeability of the BBB [75]. Tanycytes (specialized glial cells), lined at the floor of the 3rd ventricle in the MBH, are stimulated by cytokines and induce the biosynthesis of PGE2 through activation of the nuclear factor-κB (NF-κB) pro-inflammatory signaling pathway [76]. Finally, oligodendrocytes and macrophages are also recruited and participate in the sustainment of the inflammatory response [75]. The pathophysiology of hypothalamic inflammation is illustrated in Figure 1.

Inflammatory Signals Across the Gut-Brain Axis

A mechanism linking gut microbiota with their metabolites and exacerbation of the hypothalamic inflammatory status is currently being investigated. Damage of the intestinal mucosa is well documented in animals and patients with CC and may lead to transposition of bacterial components like lipopolysaccharide (LPS) to the systemic circulation [Figure 1] [77,78,79]. In animals with advanced cancer high LPS plasma levels correlated with deterioration of hypothalamic inflammation, microglia polarization and severe appetite and weight loss [12,80]. In vitro analysis showed that addition of LPS in cultured hypothalamic cells induced the release of IL-6 and this response was significantly amplified upon addition of tumor secretomes, indicating that LPS and tumor derived factors may act synergistically augmenting the inflammatory hypothalamic response [80]. It is well known that LPS induces neuroinflammation by interacting with the toll-like receptor 4 (TLR4), abundantly expressed in microglial cells, leading to phosphorylation and nuclear translocation of the NF-κB p65 subunit and the transcription of genes encoding cytokines [81,82,83]. Myeloid differentiation primary response gene 88 protein (MyD88) and TIR (Toll/interleukin-1 receptor)-domain-containing adaptor-inducing beta interferon (TRIF) are two key adaptor proteins for the TLR4-mediated downstream signaling [82,84]. Blockade of MyD88 signaling mitigated the hypothalamic inflammatory gene expression and significantly attenuated anorexia in pancreatic cancer models [28]. Likewise, TRIF deficient mice inoculated with tumor cells displayed down-regulated levels of cytokines and chemokines in the hypothalamus and improved anorexia and weight loss [27].

The Role of Hypothalamic Microglia

Several studies uncovered the contribution of glial cells in the control of energy metabolism in association with brain inflammation. Hypothalamic microglia were assigned a key role in the pathogenesis of acute sickness behavior and obesity [27,71,85,86]. In these conditions, pharmacological depletion of microglia has been reported to produce beneficial effects by attenuating hypothalamic inflammation and neuronal stress [71,85,86]. Few studies investigated the role of microglia in the development of CC. In a rodent model with implantation of the AH-130 ascites hepatoma cancer cell line, accumulation and activation of microglia were detected in both PVN and ARC where specifically increased sympathetic tone and induced the anorexigenic pathway activity [87]. Treatment with the microglia inhibitor minocycline suppressed microglia and neuronal activation and alleviated the clinical cachectic features [87]. In a murine model of pancreatic ductal adenocarcinoma (PDAC) microgliosis within the MBH was observed at an early stage of disease progression [88]. However, in this case pharmacologic microglia removal worsened cachexia indicators (anorexia, fatigue and muscle catabolism), underlying the potential protective function of microglia against PDAC induced cachexia [88]. Indeed, in vitro analysis showed that microglia responded to tumor derived factors by increasing the production of arginase-1, an enzyme with potent anti-inflammatory neuroprotective properties, and attenuating the production of IL-1 and TNF-α, both of which are implicated in neurotoxicity [88,89,90]. Even though the reason of these opposite results is not precisely understood, it is well accepted that microglia are highly heterogeneous cells and display distinguished phenotypic features when activated based on differences in the regional microenvironment. Moreover, in virtu of their plasticity these cells can reveal diversity of transcriptional profiles and functionality, depending on disease context and evolution [91]. Recent data reported the presence of two transcriptionally and functionally distinct subpopulations of activated microglia in the MBH of pancreatic cancer models with different gene expression signatures and cachexia-related responses [75]. The CD45(+) subset which expresses genes linked to a pro-inflammatory and neurotoxic profile and the CD45(-) subset which presents a transcriptional profile associated with neuronal growth, tissue remodeling and cell signaling [75]. These observations indicate that different clusters of disease related microglia coexist and at least one cluster appears to have a protective role in pancreatic cancer.

The Melanocortin System

The ARC in rodents (infundibular nucleus in humans) is located in the MBH and its role is critical for the maintenance of energy homeostasis. Within the ARC resides the MCS composed of two distinct subpopulations of neurons with opposite effects on feeding and energy balance [6]. One cluster includes the pro-opiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART) expressing neurons. POMC is a pro-hormone that is processed to biologically active peptides including the alpha-melanocyte-stimulating hormone (α-MSH), which act as an agonist at its specific subtypes melanocortin 4 receptors (MC4R) at the PVN to suppress food intake and increase energy expenditure [6]. Adjacent to POMC/CART neurons a second cluster of neurons express the orexigenic peptides Agouti-related peptide (AgRP) and neuropeptide Y (NPY) [6]. AgRP is the inverse agonist for MC3R and MC4R and antagonizes the effects of α-MSH. Neuropeptide Y (NPY) is a potent stimulator of food intake through its combined action on both the receptor subtypes Y1 and Y5 [92]. Under positive energy balance the expression of AgRP and NPY in the ARC is decreased while that of POMC and CART is enhanced. Conversely, in conditions of negative energy balance, the activity of the anorexigenic POMC/CART neurons is suppressed and the activity of NPY/AgRP neurons is promoted, resulting in reduction of the basal metabolism and increase in food consumption [7]. In the context of cancer wasting syndrome, the hypothalamus does not respond appropriately to neuroendocrine signals and the equilibrium between the neuropeptidergic circuits is dysregulated (Figure 2). Upregulated MC4R signaling was observed in the hypothalami of rodents with advanced cancer, anorexia and significant tissue loss, while central infusion of AgRP or other MC3/4-R antagonists ameliorated hypothalamic inflammation and cachexia [93,94,95,96]. This observation led to the hypothesis that interruption of the MC4R pathway may prove beneficial for the treatment of CC. Novel selective MC4R inhibitors with high bioavailability and BBB penetration capacity have been developed and when administered peripherally have been shown to protect against tumor-induced cachexia in animals [97,98].
Cytokines may directly interact and influence the activity of the MCS [Figure 2]. For example, receptors for IL-1 and LIF have been detected on POMC neurons [34,59]. In response to IL-1 administration POMC neurons increased their firing rate and the release of α-MSH from hypothalamic explants [34]. Centrally LIF-treated mice exhibited decreased food consumption associated with increased POMC activity and a-MSH secretion [59]. Conversely, IL-1 and TNF-α down-regulated the activity of AgRP-producing neurons and inhibited the release of AgRP [41].
Semaphorins of class 3 (SEMA3) are signaling secreted molecules with a regulatory role in tumor microenvironment and cancer cell behavior [99]. Semaphorin 3D (SEMA3D) has been shown to interact with its receptors neurophilin and plexin located on POMC neurons to drive the development of the hypothalamic circuit and energy balance [Figure 2] [100]. In a recent paper increased SEMA-3D expression was reported in patients and animals with CC which was positively related to increased hypothalamic POMC levels [101]. Mice with deficiency of SEMA3D showed decreased POMC neural activity and improvement of cachexia parameters [101].
The levels of hypothalamic POMC m-RNA have been found to be low, high or even unchanged among different cancer models or vary in the same model as the disease progresses [23,24,30,60,75,102,103,104,105,106]. It has been postulated that acute or chronic inflammatory stimuli may exert opposing signals on POMC expression. In conditions of acute inflammation POMC expression is induced, whereas in chronic inflammation POMC expression is suppressed. Administration of LPS (a typical model that resembles acute inflammation) in animals, induced an extensive cytokine response that promoted POMC expression, leading to an anorexic state and increased energy expenditure [107]. In the contest of malignancy, early (acute) or advanced (chronic) stage of the disease is associated with high or reduced POMC levels, respectively. Cernackova et al. found increased POMC transcript levels at day 21 in fibrosarcoma bearing Wistar rats, before cachexia was detected, and decreased POMC levels at day 28 when cachectic manifestations were remarkable [30]. Likewise, Suzuki et al. noted a pronounced decrease of POMC expression in hypothalamus of gastric cancer bearing rats only in advanced-stage cachexia with severe anorexia [105]. A previous report revealed that the p65 subunit of the transcription factor NF-κB binds to the POMC promoter and activate its transcription in acute inflammatory conditions. However, in chronic inflammatory states due to increased methylation at and near the p65 binding site within the POMC promoter, the p65 subunit is unable to interact with the promoter, resulting in failure of the NF-κB-induced POMC transcription. At the same time p65 interacts with the phosphorylated signal transducer and activator of transcription 3 (STAT3) preventing its binding to the POMC promoter, further repressing its transcriptional activation [108].
Lipocalin-2 (LCN2) was recently identified as an endogenous osteoblast-derived appetite-suppressing factor with central action [109]. Mosialou et al. showed that in normal mice when LCN2 was injected intraperitoneally was able to cross the BBB and inhibit food intake through a MC4R signaling dependent manner in neurons located in the PVN and VMH [Figure 2] [109]. Elevated hypothalamic and circulating levels of LCN2 have been detected in murine cancer models and associated with late cachexia stage [12,29,75,96]. Conversely, tumor bearing mice with genetic deletion of LCN2 showed improvement of energy intake and tissue wasting [75,96]. It has been reported that tumor cells stimulate the neutrophils of the bone marrow compartment to produce and secrete LCN2 and that this circulating LCN2 is able to penetrate the BBB and negatively regulate feeding behaviour [96]. Huisman et al. reported that in a pancreatic cancer murine model LCN2 was a strong stimulator of hypothalamic inflammation and affected gene expression in POMC neurons, but without affecting POMC expression itself [75]. Since anorexia in this model occurred independently of POMC expression and could be reversed with melanocortin antagonists, the authors concluded that LCN2 is likely to bind to and activate the MC4R, thus by-passing the physiologic melanocortin signaling pathway [96,97]. Further studies are warranted in order to determine the potential interaction between LCN2 and MC4R in pathologic conditions.

Neurotransmitters Implicated in Energy Balance

1. NPY

NPY acts mainly in the PVN and its release is associated with increased food intake. NPY secretion is stimulated in conditions of negative energy balance such as fasting, exercise and suppressed after refeeding [110]. In CC the NPYergic system seems to be dysfunctional [111]. Central administration of NPY does not elicit feeding response in tumor-bearing rodents compared to non-tumor bearing counterparts [112]. The levels of NPY m-RNA are either unaltered or increased in anorexic animals but without a compensatory increase in food intake [23,30,60,75,103,111,113,114,115]. Various hormonal and metabolic signals have been reported to affect the synthesis and secretion of NPY. Leptin and lactate decrease NPY m-RMA levels through AMPK inhibition, whereas ghrelin and glucocorticoids (GC) induces NPY gene expression through AMPK activation [116,117,118,119]. However, in contrast to elevated NPY transcript levels in hypothalamus, reduced protein levels are detected in the PVN, suggesting an impaired NPY transport and release at this specific region [120,121]. The increased serotonergic tone may contribute to this by interfering with NPY signaling at the post transcriptional level and repress its secretion [115]. Leptin has also been shown to suppress NPY secretion in hypothalamic cell lines [116].

2. 5-hydroxytryptamine

The neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin has long been considered as a potent anorectic agent with central action. There is evidence that the serotonergic pathway originates from the raphe nucleus in the brainstem and lesions of these nuclei induce hyperphagia [122,123]. 5-HT neurons in the raphe nuclei project to the ARC where they regulate the neural activity of the MCS [122]. 5-HT leads to direct activation of the POMC neurons via interaction with 5-HT2c, and inhibition of the NPY/AgRP neurons via interaction with 5-HT1b subtype receptors [Figure 2] [124,125]. In experimental cancer systems elevated expression levels of 5-HT and HT1b have been observed in hypothalamic nuclei and correlated inversely with food consumption [126,127,128,129]. Tumor removal normalized these alterations and restored appetite [127,128]. Intrahypothalamic delivery of the non-selective 5-HT antagonist mianserin improved anorexia significantly in cachectic animals with cancer [130]. Cytokines may interfere with the 5-HT turnover or regulate the plasma pool of tryptophan, the precursor molecule of 5-HT [110]. IL-1 when injected peripherically reduced food intake and increased plasma tryptophan, suggesting an increase in brain 5-HT synthesis [131]. High plasma and hypothalamic levels of tryptophan and the metabolite 5-hydroxy indoleacetic acid (5-HIAA), marker of 5-HT release, have been reported in both tumor-bearing rats and anorectic cancer patients [132,133].

3. Orexins

Orexins (A and B) are hypothalamic neuropeptides involved in the regulation of multiple functions like sleep-wake cycle, autonomic function, feeding behavior and energy homeostasis [134]. Orexin-secreting neurons are placed mainly in the LHA/perifornical area (PFA) and are activated in response to NPY positive projections originating from ARC neurons [135]. They in turn, project and release their product to other hypothalamic centers, including PVN, ARC and NTS. Orexin neurons in the LHA sense and respond to peripheral circulating metabolic signals such as glucose, leptin and ghrelin [Figure 2] [134]. Central delivery of orexin-A in rats enhanced food intake, although continuous infusion did not produce substantial changes on feeding and body weight [136,137]. Prepro-orexin m-RNA levels are induced during periods of negative energy balance, such as periods of fasting [136,138]. There is evidence that LPS-induced hypothalamic inflammation disrupts the orexigenic signaling in the LHA and leads to reduced physical activity and hypophagia in animals [139]. In a similar manner, tumor-induced inflammation in anorectic rats was paralleled by a reduction in the number of orexin mRNA-expressing neurons, predominantly in the PFA [139]. The anorectic chemotherapeutic agent cisplatin has been associated with increased hypothalamic levels of proinflammatory cytokines and reduction of prepro-orexin m-RNA [86,140]. Direct delivery of orexin-A to the ARC enhanced significantly the feeding response and the use of neuropeptide Y1 receptor antagonist abolished this effect [140]. These findings indicate that orexin signaling in the ARC stimulates the feeding response via an NPY-dependent pathway.

4. Nesfatin-1

Nesfatin-1 is an 82-amino acid polypeptide that is cleaved from the precursor protein nucleobindin-2 (NUCB2) [141]. Nesfatin-1/NUCB2 was first detected in rat brains, in the PVN, ARC and NTS and latter in various peripheral tissues [141,142]. Rats with deficiency of Nesfatin-1/NUCB2 in the PVN increased feeding, fat accumulation and body weight [143]. Overexpression of Nesfatin-1/NUCB2 has been correlated with cancer invasion and metastatic potential [144,145]. Elevated Nesfatin-1/NUCB2 m-RNA levels in the PVN have been reported in tumor-bearing mice with anorexia implying a role for this molecule in the etiology of the syndrome [146]. Several mechanisms involved in the Nesfatin-1/NUCB2-induced anorexia have been proposed. Central administration of SHU9119, a melanocortin-3/4 receptor antagonist, abolished the anorexia induced by Nesfatin-1/NUCB2, suggesting a possible interaction with the MCS [147]. Increase of the oxytocinergic signaling from PVN neurons to POMC neurons in the NTS, interaction with the corticotropin releasing factor (CRF) receptor system and down-regulation of the NPY-expressing neurons in the ARC have also been reported [148,149,150]. Finally, Nesfatin-1/NUCB2 has been shown to evoke a sympatho-excitatory response through extracellular signal regulated kinase (ERK)-dependent signaling in PVN-CRF neurons and enhance fat lipolysis and fatty-acid oxidation in skeletal muscle in pathologic contexts other than CC [151,152].

Peripheral Hormone Signals: Leptin and Ghrelin

Leptin is a protein hormone derived from the adipocytes involved in satiety promotion and increase in energy expenditure [153]. Leptin signals in the cell by binding to its transmembrane receptors (Lep-R) and activating the JAK/STAT pathway [154]. Leptin interacts with both NPY/AgRP and POMC neurons in the ARC producing opposing effects, as well as with neurons expressing the MC4R in the PVN [Figure 2] [155,156]. Low leptin plasma levels have been reported among patients and animals with CC but without a concomitant compensatory stimulation of appetite or weight gain [104,157,158,159]. There is evidence that cytokines that share the same post receptor pathway with leptin, are able to upregulate the anorexigenic and down-regulate the orexigenic pathways by mimicking leptin action. In particular, members of the IL-6 family induce the phosphorylation of STAT3, similar to leptin and have been demonstrated to trigger anorexia-cachexia in cancer animal models, providing an explanation for the persistence of anorexia and body weight loss, in spite of decreased leptin concentration [51,160]. Treatment with molecules that inhibit JAK activity suppressed the anorexia associated with cancer in animals, inhibited lipolysis and improved survival and all these effects were accompanied by the reduction of STAT3 phosphorylation in hypothalamic and adipose tissues [51].
Ghrelin, is an endogenous stomach derived ligand with high affinity for the growth hormone (GH) secretagogue receptor (GHS-R) [161]. Ghrelin promotes weight gain by increasing appetite and decreasing energy expenditure [162]. Independently of its action in regulating the activity of the pituitary GH releasing neurons, ghrelin directly activates the orexigenic NPY/AgRP neurons which express the GHS-R [163,164]. Ghrelin is also able to inhibit POMC neurons indirectly through an increase of the inhibitory GABAergic tone originating from the NPY/AgRP neurons [165,166]. Additionally, ghrelin is able to act peripherically by stimulating the GHS-Rs located at the vagal afferent terminals which in turn transmit the signal to the hypothalamus [167]. Ghrelin serum levels are frequently found increased in cachectic patients with cancer and in anorectic tumor carrying animals. However due to an altered ghrelin signaling (called ghrelin resistance) appetite remains suppressed [Figure 2] [93,168,169,170,171,172]. It has been postulated that the anorexigenic proinflammatory cytokines can interfere with the appetite stimulatory effect induced by ghrelin [172]. Modulation of the orexigenic ghrelin signaling in anorectic tumor bearing rats due to hypothalamic interaction of 5-HT and CRF via the 5-HT2c has also been reported [10]. Defects at the receptor level might also influence the physiologic ghrelin signaling. In support of this hypothesis, reduced expression of the GHS-R has been detected in animals treated with the anorexigenic agent cisplatin and oral administration of 5-HT2cR antagonist, enhanced ghrelin sensitivity through up-regulation of the hypothalamic GHS-R levels and attenuated anorexia [173]. However, in tumor-bearing animals the levels of hypothalamic GHS-R were found to be either similar to control animals or elevated and normalized after ghrelin administration at high doses [171,172]. Moreover, when ghrelin was given to patients and animals with cancer, food intake was stimulated, suggesting that presumably further increase of plasma ghrelin levels by exogenous administration may overcome the endogenous encountered resistance to the peptide, resembling that way the treatment for insulin-resistant state in type II diabetes by peripheral insulin delivery [169,171,174,175]. Ghrelin or ghrelin mimetics in animals with CC, along with the positive impact on orexigenic peptides exert also an anti-inflammatory hypothalamic action as reported by the decrease of IL-1 receptor transcripts levels [175].

Neuroendocrine and Autonomic Regulation

The neuroendocrine system is regulated by hypothalamic neurons that send projections to the ME and secrete neurohormones into the portal hypophyseal system to excite cells in the anterior pituitary gland (adenohypophysis). Among these trophic factors, CRF is released by neurons located within the parvocellular zone of the PVN and stimulates the secretion of adrenocorticotropic hormone (ACTH) from the pituitary. ACTH induces the adrenal cortex to produce GC (cortisol in humans and corticosterone in rodents) which in turn exerts a negative feed-back control suppressing the hypothalamic-pituitary-adrenal axis (HPA) [176].
It is well accepted that GCs play a crucial role in muscle wasting by regulating specific intracellular signaling pathways which stimulate protein catabolism and inhibit protein synthesis [177]. Rise in endogenous GC levels have been reported in both cancer patients and tumor bearing animals and correlated with the severity of cachexia [11,12,30,178,179,180]. In adenomatous polyposis coli (APC) cachectic mice a rise in corticosterone levels in serum and in skeletal muscle was associated with the induction of the transcription of GC-responsive genes that promote muscle protein degradation (called atrogenes) and down-regulate phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) anabolic pathway [11].
Although GCs act as downstream effectors of the HPA axis the upstream mechanism by which HPA is activated in cancer cachexia is unknown. CRF possess a strong hypophagic action and has assumed particular relevance in the setting of cancer [10,11,26,120]. In mice with terminal stage pancreatic cancer, severe muscle loss was associated with elevated hypothalamic CRF gene expression [26]. I.c.v. administration of a CRF antagonist in rats inoculated with AH-130 ascites hepatoma cells increased feeding, suggesting that the CRF system is activated in malignancy [10].
Cytokines such as IL-1, IL-6, TNF-α have been shown to directly stimulate the expression of the CRF gene in hypothalamic 4B cells [49,181,182]. Central administration of serum anti-CRF abolished the IL-1-induced anorexia in Wistar rats and depletion of endogenous IL-6 was associated with reduced production of CRF [49,183]. The brain derived neurotrophic factor (BDNF) is a molecule with a central role in energy control also able to stimulate the anorexigenic CRF system. Single or continuous i.c.v. delivery of BDNF upregulated the CRF m-RNA levels predominantly in the PVN and local infusion of the a-helical CRF receptor antagonist counteracted the appetite suppressive effect evoked by BDNF [184].
Ultrastructural analysis revealed neuronal intercommunications between 5-HT axons and CRF-containing neurons in the PVN, indicating that a possible interaction between the central serotonergic system and CRF synthesis may exist [185]. In physiologic murine models, 5-HT agonists enhanced c-fos immunoreactivity in CRF-containing neurons in the parvocellular zone and increased CRF m-RNA expression [186]. The administration of 5-HT2cR antagonists decreased hypothalamic CRF level and ameliorated anorexia and body weight loss in tumor-bearing rats [10].
CRF positive neurons in the PVN also express the MC4R [187]. Several studies investigated the potential involvement of these receptors in the CRF induced anorexia with disaccording results [188,189]. Selective blockage of the MC4-R in rats did not affect the CRF-induced inhibition of food intake suggesting that the anorectic effect of CRF is independent of signaling pathways involving the MC4R [188]. On the contrary, the appetite suppressive effect following delivery of a synthetic α-MSH was abolished when a CRF receptor antagonist was used [189]. Experiments in CRF knock-out mice revealed that CRF was involved in the early phase of the α-MSH induced anorexia but not in the late phase, implying that other endogenous ligands of the CRF family might be responsible for the late anorexic effect [189]. A schematic representation of the molecules involved in the activation of the HPA axis in CC is presented in Figure 3.
The parvocellular PVN provides an important sympathoexcitatory output through connections with brainstem centers and pre-ganglionic neurons in the spinal cord as well as with local intrahypothalamic neurocircuits. Activation of the PVN-sympathetic adipose circuit has been reported in chronic restraint stress [190]. Increased sympathetic drive is documented in humans and experimental models of tumor cachexia and it is associated with white adipose tissue browning, resulting in lipid mobilization and augmented non-shivering thermogenesis [Figure 3] [8,191].
BDNF signaling in the PVN plays a key role in the regulation of sympathetic activity and energy expenditure. Wang et al. showed that leptin signaling in the ARC is able to regulate sympathetic innervation of adipose tissue through a downstream BDNF-expressing population of neurons in the PVN [192]. These neurons are placed in the medial and posterior part of the PVN and project their axons to the sympathetic preganglionic neurons in the intermedio lateral column of the spinal cord. BDNF is released at this site where interacts with its corresponding tropomyosine receptor tyrosine kinase B (TrkB), thereby stimulating BAT thermogenesis [192,193]. In addition, BDNF- positive neurons in the PVN receive dopaminergic projections from neurons located in the Substantia Nigra (SN). Bilateral lesions at this level increased BDNF release in PVN which in turn increased catabolism and thermogenesis in BAT, underlying the importance of upstream brain nuclei in the modulation of BDNF activity and BAT metabolism [194]. Even though remarkable increase in BDNF hypothalamic expression has been detected in anorectic tumor bearing rats, studies investigating the activity of BDNF in the PVN in the setting of CC are missing [105].
LIF receptors are also expressed in neurons in the PVN [52]. In several mouse allograft cancer models Xu et al. showed that LIF was able to trigger neuronal activation in several brain regions including PVN [Figure 3] and promote tumor progression through a mechanism involving sympathetic activation and peripheral immune cellular response [52]. Sympathetic ablation led to inhibition of tumor growth without affecting significantly the LIF-mediated neuronal activation of the PVN, suggesting that cancer affects upstream brain centers to modulate the sympathoexcitatory output [52]. However, besides the clear antitumor effect, the cachectic parameters or the effects on adipose tissue were not directly evaluated in the study and additional work investigating the correlation between LIF-induced sympathetic response and adipose tissue dysfunction is required.

Conclusions

CC is a multifactorial chronic condition related to abnormalities of the central physiological mechanisms that regulate food intake and energy balance. The hypothalamus has been recognized as an essential center that receives peripheral blood-borne signals and messages from other important brain structures which it transduces in perturbated neuronal signaling, abnormal neuroendocrine response and metabolic dysregulation. Hypothalamic inflammation has been shown to promote anorexia by triggering changes in orexigenic and anorexigenic neural circuits and induce energy deficit. Understanding the complex interrelationship between cytokines, tumor-derived factors and brain neurotransmitters and neuropeptides could not only shed light on the underlying pathophysiology of the disorder but also prove indispensable in unveiling the potential therapeutic interventions for the wasting syndrome associated with cancer. Disrupting neural signaling pathways and interfering pharmacologically with cytokine action might be therapeutically exploited in order to ameliorate the cachexia symptoms.

Conflict of Interests

There is not competing interest to declare

Author Contributions

Figures were drawn by Dimitrios Stagikas. Konstantinos I. Tsamis revised the manuscript. All authors contributed equally to the creation of the manuscript and approved the final version of the paper

Funding

This study was not supported by any sponsor or funder

Institutional Review Board Statement

Not applicable for this manuscript

Informed Consent Statement

The authors declare their consent for publication of the review article in Acta Physiologica

Data Availability Statement

No datasets were generated or analysed during the current study

Acknowledgments

Figures were created using the free graphic editor Inkscape. Specific icons and images were provided by the open-source databases smart.servier.com and reactome.com

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Figure 1. Hypothalamic inflammation in the pathophysiology of cancer cachexia (CC). Inflammatory mediators and tumor derived factors create a systemic inflammatory state which impacts on peripheral organs i.e. muscle, adipose, liver, heart and gut. The disruption of the intestinal barrier leads to the release of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) in the circulation. Both cytokines and LPS act through the blood brain barrier (BBB) at the hypothalamus where they induce microglial activation and increase the production of pro-inflammatory molecules via the nuclear factor-κB (NF-κB) pathway. Tanycytes participate in this process by secreting inflammatory and anorexigenic molecules such as prostaglandin-E2 (PGE2) and inflamed endothelial cells display altered expression of transmembrane proteins and cell adhesion molecules leading to alteration of the BBB permeability, which further contributes to the exacerbation of the pro-inflammatory environment. Chemokines and adhesion molecules recruit macrophages in the hypothalamus which secrete secondary pro-inflammatory mediators. Oligodendrocytes are also activated and upregulate the expression of genes involved in cell metabolism and adhesion. Finally, peripheral inflammatory signals are also delivered through the sensory vagal afferent fibers to the brainstem centers which are interconnected with the hypothalamus. Collectively, the proper function of the hypothalamic neuronal circuits is affected, translating in altered feeding behavior and energy expenditure. 3V third ventricle; ARC arcuate nucleus; c-fos; CSF cerebrospinal fluid; ECM extracellular matrix; IL-1 interleukin-1; IL-6 interleukin-6; LCN2 lipocalin-2; LIF leukemia inhibitory factor; ME media eminence; NF-κB nuclear factor-κB; TLR4 toll-like receptor 4; TNF-α tumor necrosis factor-α
Figure 1. Hypothalamic inflammation in the pathophysiology of cancer cachexia (CC). Inflammatory mediators and tumor derived factors create a systemic inflammatory state which impacts on peripheral organs i.e. muscle, adipose, liver, heart and gut. The disruption of the intestinal barrier leads to the release of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) in the circulation. Both cytokines and LPS act through the blood brain barrier (BBB) at the hypothalamus where they induce microglial activation and increase the production of pro-inflammatory molecules via the nuclear factor-κB (NF-κB) pathway. Tanycytes participate in this process by secreting inflammatory and anorexigenic molecules such as prostaglandin-E2 (PGE2) and inflamed endothelial cells display altered expression of transmembrane proteins and cell adhesion molecules leading to alteration of the BBB permeability, which further contributes to the exacerbation of the pro-inflammatory environment. Chemokines and adhesion molecules recruit macrophages in the hypothalamus which secrete secondary pro-inflammatory mediators. Oligodendrocytes are also activated and upregulate the expression of genes involved in cell metabolism and adhesion. Finally, peripheral inflammatory signals are also delivered through the sensory vagal afferent fibers to the brainstem centers which are interconnected with the hypothalamus. Collectively, the proper function of the hypothalamic neuronal circuits is affected, translating in altered feeding behavior and energy expenditure. 3V third ventricle; ARC arcuate nucleus; c-fos; CSF cerebrospinal fluid; ECM extracellular matrix; IL-1 interleukin-1; IL-6 interleukin-6; LCN2 lipocalin-2; LIF leukemia inhibitory factor; ME media eminence; NF-κB nuclear factor-κB; TLR4 toll-like receptor 4; TNF-α tumor necrosis factor-α
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Figure 2. Theoretical model of neurofunctional mechanisms in CC. Molecules such as IL-1, semaphorin 3D (SEMA 3D) and LIF stimulate the anorexigenic POMC neurons. Conversely, IL-1 and TNF-α inhibit the orexigenic NPY/AgRP neurons, ultimately leading to suppresion of appetite. Leptin and ghrelin also target neurons in the ARC. Low leptin and high ghrelin levels, are frequently encountered in CC in order to counterbalance the energy deficit. However, due to an altered hypothalamic responsiveness, “resistance” to both hormones is observed. NPY/AgRP and POMC axons from the ARC project and regulate the activity of MC4R neurons in the PVN and orexin producing neurons in the lateral hypothalamic area/perifornical area (LHA/PFA). The tumor derived molecule lipocalin-2 (LCN-2) has been shown to suppress appetite through binding to its receptor MC4R in neurons in the PVN. On the contrary, molecules with MC4R antagonistic properties have been proven to be safe and effective in reversing CC symptoms in animals. Orexin neurons in the LHA/PFA respond to peripheral metabolic stimuli (leptin, ghrelin, glucose) and modulate feeding response by affecting the NPY neurons in the ARC. Suppression of the orexigenic signaling in the PFA has been reported in tumor induced inflammation models. Finally, serotonergic neuronal fibers originating from the nuclei del raphe activate POMC and inhibit NPY/AgRP neurons in the ARC via interaction with the 5-hydroxytryptamine (5-HT) stimulatory (5-HT2c) and inhibitory (5-HT1b) receptor subtypes, respectively. Enhanced 5-HT signaling is also well documented in CC. Green arrows: increase feeding, red arrows: decrease feeding, (+): stimulatory, (-): inhibitory
Figure 2. Theoretical model of neurofunctional mechanisms in CC. Molecules such as IL-1, semaphorin 3D (SEMA 3D) and LIF stimulate the anorexigenic POMC neurons. Conversely, IL-1 and TNF-α inhibit the orexigenic NPY/AgRP neurons, ultimately leading to suppresion of appetite. Leptin and ghrelin also target neurons in the ARC. Low leptin and high ghrelin levels, are frequently encountered in CC in order to counterbalance the energy deficit. However, due to an altered hypothalamic responsiveness, “resistance” to both hormones is observed. NPY/AgRP and POMC axons from the ARC project and regulate the activity of MC4R neurons in the PVN and orexin producing neurons in the lateral hypothalamic area/perifornical area (LHA/PFA). The tumor derived molecule lipocalin-2 (LCN-2) has been shown to suppress appetite through binding to its receptor MC4R in neurons in the PVN. On the contrary, molecules with MC4R antagonistic properties have been proven to be safe and effective in reversing CC symptoms in animals. Orexin neurons in the LHA/PFA respond to peripheral metabolic stimuli (leptin, ghrelin, glucose) and modulate feeding response by affecting the NPY neurons in the ARC. Suppression of the orexigenic signaling in the PFA has been reported in tumor induced inflammation models. Finally, serotonergic neuronal fibers originating from the nuclei del raphe activate POMC and inhibit NPY/AgRP neurons in the ARC via interaction with the 5-hydroxytryptamine (5-HT) stimulatory (5-HT2c) and inhibitory (5-HT1b) receptor subtypes, respectively. Enhanced 5-HT signaling is also well documented in CC. Green arrows: increase feeding, red arrows: decrease feeding, (+): stimulatory, (-): inhibitory
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Figure 3. Activation of the HPA axis and sympathetic response in CC. Cytokines, nesfatin-1, brain derived neurotrophic factor (BDNF) and 5-HT induce the expression of the hypophagic corticotropin releasing factor (CRF) in the PVN. It is not clear the interaction between the CRF system and the melanocortin signaling pathway. CRF is transported to the anterior pituitary where stimulates the secretion of adrenocorticotropic hormone (ACTH). ACTH triggers the adrenal glands to produce glucocorticoids (GCs) which in turn affect the transcription of genes involved in muscle catabolism and hepatic metabolism. PVN plays also a crucial role in the regulation of the hypothalamic-sympathetic-adipose circuit. Increased sympathetic outflow and fat remodelling have been reported in CC. A cluster of pre-autonomic BDNF neurons in the PVN send projections to pre-ganglionic sympathetic neurons in the spinal cord in order to induce brown adipose tissue (BAT) thermogenesis and increased hypothalamic BDNF levels have been reported in anorectic tumor bearing rats. LIF originated from tumor cells acts on PVN neurons and increase the sympathetic tone which in turn promotes tumor growth
Figure 3. Activation of the HPA axis and sympathetic response in CC. Cytokines, nesfatin-1, brain derived neurotrophic factor (BDNF) and 5-HT induce the expression of the hypophagic corticotropin releasing factor (CRF) in the PVN. It is not clear the interaction between the CRF system and the melanocortin signaling pathway. CRF is transported to the anterior pituitary where stimulates the secretion of adrenocorticotropic hormone (ACTH). ACTH triggers the adrenal glands to produce glucocorticoids (GCs) which in turn affect the transcription of genes involved in muscle catabolism and hepatic metabolism. PVN plays also a crucial role in the regulation of the hypothalamic-sympathetic-adipose circuit. Increased sympathetic outflow and fat remodelling have been reported in CC. A cluster of pre-autonomic BDNF neurons in the PVN send projections to pre-ganglionic sympathetic neurons in the spinal cord in order to induce brown adipose tissue (BAT) thermogenesis and increased hypothalamic BDNF levels have been reported in anorectic tumor bearing rats. LIF originated from tumor cells acts on PVN neurons and increase the sympathetic tone which in turn promotes tumor growth
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