NPY and brain monoamines in the pathogenesis of cancer anorexia

Nutrition 24 (2008) 802– 805 www.elsevier.com/locate/nut

NPY and brain monoamines in the pathogenesis of cancer anorexia Alessandro Laviano, M.D.a,*, Akio Inui, M.D., Ph.D.b, Michael M. Meguid, M.D., Ph.D.c, Alessio Molfino, M.D.a, Caterina Conte, M.D.a, and Filippo Rossi Fanelli, M.D.a a

b

Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy Department of Behavioral Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan c Department of Surgery, SUNY Upstate Medical University, Syracuse, New York, USA Manuscript received and accepted June 3, 2008.

Abstract

Cancer anorexia frequently characterizes the clinical journey of patients with cancer and affects patients’ morbidity, mortality, and quality of life. A constellation of symptoms concur to the diagnosis of anorexia, and early satiety, changes in taste/smell, and nausea are the more frequently reported. The pathogenesis of cancer anorexia is multifactorial, but accumulating evidence indicates that the hypothalamic melanocortin and neuropeptide Y systems become resistant to peripheral inputs. This results in increased melanocortin activity and reduced neuropeptide Y function, thereby leading to the promotion of catabolic stimuli (i.e., reduced energy intake, increased energy expenditure, possibly increased muscle proteolysis, and adipose tissue loss). Interestingly, hypothalamic proinflammatory cytokines and serotonin, among other factors, are key in triggering hypothalamic resistance. In the clinical setting, cancer anorexia develops with heterogeneous presenting symptoms (i.e., early satiety and/or nausea and/or changes of taste) and varying degrees of severity. Available evidence suggests that the constellation of symptoms characterizing this syndrome should be considered, at least in part, as different phenotypes of common neurochemical/metabolic alterations in the presence of a chronic inflammatory state. © 2008 Elsevier Inc. All rights reserved.

Keywords:

Anorexia; Food intake; Melanocortin; Cytokines; Serotonin

Introduction Cancer anorexia is clinically characterized by a number of signs and symptoms interfering with energy intake (i.e., reduced appetite, early satiety, changes in taste/smell) that contribute to the development of weight loss and wasting of fat and muscle masses (i.e., cachexia), eventually leading to increased morbidity and mortality and reduced quality of life. It should be acknowledged that in the clinical setting, patients with cancer usually present with the anorexia– cachexia syndrome rather than with solely anorexic or cachectic symptoms. Interestingly, accumulating evidence suggests that anorexia and cachexia represent in part different phenotypes of common neurochemical/metabolic alterations. Indeed, body weight loss and poor nutritional status are reliable predictors of mortality in chronic diseases [1]. Weight loss due to cachexia is not completely accounted for * Corresponding author. Tel.: ⫹39-0649973902; fax: ⫹39-06-4440806. E-mail address: [email protected] (A. Laviano). 0899-9007/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2008.06.005

by the degree of anorexia and reduced food intake [2]. Notwithstanding this, anorexia represents an independent negative prognostic factor [3], suggesting the existence of a common pathway linking anorexia and cachexia.

Neuropeptide Y and cancer anorexia Under physiologic conditions, the homeostasis of food intake and body weight is controlled by complex and redundant mechanisms. Neural, metabolic, and humoral signals from peripheral tissues inform the brain whether energy stores are being repleted or depleted. The hypothalamus receives and integrates peripheral signals [4]. Within the hypothalamus, the arcuate nucleus in rodents (i.e., the infundibular nucleus in humans), situated between the third ventricle and the median eminence, is considered to act as a primary sensor of alterations in energy stores to control appetite and body weight. Involved in this role are two distinct subsets of arcuate neurons.

A. Laviano et al. / Nutrition 24 (2008) 802– 805

The first population of neurons expresses proopiomelanocortin (POMC). POMC is a polypeptide that is cleaved into smaller biologically active peptides, among them the melanocortins. The biological effects of melanocortins are mediated through a family of melanocortin receptors [5]. Among them, melanocortin-4 receptor (MC4R) appears to be a critical component of the homoeostatic circuit that regulates energy balance by mediating anorectic and catabolic responses. The second subset of arcuate neurons expresses the potent orexigenic peptide neuropeptide Y (NPY) and agoutirelated protein (AgRP). Interestingly, AgRP is the endogenous antagonist of MC4Rs, thereby antagonizing the anorexigenic effects of melanocortins. This evidence underlines the reciprocal functional relation between the two subsets of arcuate neurons. The POMC and NPY/AgRP neurons then project to related hypothalamic nuclei to regulate energy intake and metabolism. There is general agreement that energy intake and body weight are controlled by a complex circuitry involving POMC and NPY/AgRP neurons [4]. In the presence of excess energy, POMC neurons are activated and trigger the release of melanocortins from POMC axon terminals, which activate MC4R, thereby leading to suppressed food intake and increased energy expenditure. Simultaneously, the activity of the arcuate AgRP/NPY system is suppressed, which would otherwise antagonize the effects of melanocortins on MC4R. In contrast, in times of energy depletion, the activity of anorexigenic POMC neurons is decreased but the activity of orexigenic NPY/AgRP neurons is increased. The anorexia– cachexia syndrome is characterized by hypothalamic resistance to normal homeostatic feedback. The hypothalamic resistance to these peripheral signals appears to be mediated by the persistent activation of POMC/ Cocaine-Amphetamine Regulated Transcript (CART) neurons. However, central infusion of AgRP in cachectic animals ameliorates anorexia and improves body composition [6]. This suggests that decreased activity of NPY/AgRP neurons should parallel the hyperactivation of POMC/ CART neurons during disease. Immunocytochemical studies in tumor-bearing rats with anorexia– cachexia show decreased NPY innervation of hypothalamic nuclei [7], which is reversed by tumor resection [8]. Direct measurement of NPY concentrations in the hypothalamus of tumor-bearing rats with anorexia– cachexia reveals a significant decrease of this orexigenic peptide [9], despite increased mRNA levels for NPY also being reported [10]. Furthermore, mRNA levels and immunostaining of the NPY receptor, the Y [1] receptor, are decreased in the hypothalamus of tumorbearing rats [10], whereas tumor resection restores normal hypothalamic NPY levels [11]. In humans, data on hypothalamic NPY levels and activity during wasting diseases are lacking. However, significantly lower plasma levels of NPY have been measured in anorectic patients with cancer when compared with controls [12]. Furthermore, animal studies show that megestrol ace-

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tate, an orexigenic drug used in the treatment of human anorexia– cachexia, increases hypothalamic NPY levels [13]. Based on the large and consistent amount of evidence, it appears that the anorexia– cachexia syndrome is related, at least in part, to dysfunction of the melanocortin system, consisting of hyperactivity of POMC/CART neurons and decreased activity of NPY/AgRP neurons, leading to hypothalamic resistance to peripheral inputs signaling energy depletion.

Brain monoamines and cancer anorexia The mechanisms responsible for the dysfunction of the coordinated activities of POMC and NPY/AgRP neurons have been investigated in experimental studies, and results suggest the involvement of proinflammatory cytokines and hypothalamic serotonergic neurons. The role of proinflammatory cytokines, and particularly interleukin-1 (IL-1) and tumor necrosis factor-␣, in the pathogenesis of the anorexia– cachexia syndrome has been recognized for many years [14]. In tumor-bearing rats with anorexia, hypothalamic IL-1 mRNA expression is significantly increased [15]. Also, IL-1 levels in the cerebrospinal fluid of anorectic tumor-bearing rats are increased and inversely correlate with energy intake [16], and intrahypothalamic injection of the IL-1 receptor antagonist ameliorates anorexia in the same experimental model [17]. In humans, IL-1 appears to play a significant role in mediating anorexia– cachexia because megestrol acetate has been shown to exert its effects by reduced expression of IL-1 by mononuclear cells [18], beyond its influence on hypothalamic NPY concentrations [13]. Serotonin is a classic neurotransmitter that contributes to the regulation of numerous behavioral and physiologic functions, including energy balance [19]. Its role in mediating satiety through its effects in the hypothalamus is well established [20]. This prompted studies on its influence in inducing anorexia during cancer. In experimental tumor models, the onset of anorexia is associated with increased hypothalamic serotonin levels, as assessed by in vivo microdialysis [21], and increased expression of serotonin receptors (5-HTRs) [8]. Strengthening the link between serotonergic neurotransmission and cancer anorexia, tumor resection has been demonstrated to restore energy intake, which is associated to normalized hypothalamic serotonin concentrations [21] and receptor expression [8]. Furthermore, intrahypothalamic injection of the serotonin antagonist mianserin improves energy intake in anorectic tumorbearing rats [17]. In humans, the role of serotonin in cancer anorexia has been inferred by detecting increased plasma and cerebrospinal fluid levels of the precursor of serotonin, the amino acid tryptophan, in anorectic-cachectic patients with cancer [22]. Also, therapeutic strategy aiming at reducing the brain supply of tryptophan has met with improved energy intake

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and nutritional status not only in patients with cancer but also in patients with uremia and liver cirrhosis [23]. Intriguingly, the anorectic effects of serotonin appear to be mediated by the melanocortin system. The administration of fenfluramine, a serotonin re-uptake inhibitor, has been shown to activate central melanocortin pathways [24]. More recently, 5-HT2cR and 5-HT1bR have been shown to display a complementary distribution within the arcuate nucleus: 5-HT2cRs are expressed in anorexigenic POMC/ CART neurons and 5-HT1bRs are expressed in orexigenic NPY/AgRP neurons [25]. The use of agonists at these receptors influenced the activity of both cell populations in a reciprocal manner, because they hyperpolarized NPY/AgRP neurons and suppressed inhibitory postsynaptic potentials in POMC/CART neurons [25]. Serotonin and IL-1 do not appear to represent separate pathways influencing the activity of the central melanocortin system. Peripheral infusion of IL-1 induces anorexia and raises brain tryptophan levels, thereby suggesting increased serotonin synthesis [26]. Also, IL-1 intrahypothalamic injection depresses food intake and increases the release of serotonin [27]. These data indicate that, during catabolic states, increased hypothalamic expression of IL-1 occurs in conjunction with increased release of serotonin. Serotonin and IL-1 interact within the arcuate nucleus to influence the activity of the melanocortin system, yielding and maintaining the inhibition of NPY/AgRP neuronal activity and the suppression of the inhibition of POMC/CART neurons. These biochemical events facilitate the release of the endogenous MC4R agonist, ␣-Melanocyte Stimulating Hormone, and suppress the release of the endogenous MC4R antagonist, AgRP, thus resulting in dysfunction of the melanocortin system.

Conclusion In recent years, our knowledge of the neural mechanisms regulating the onset and progression of cancer anorexia has significantly improved. More recently, intriguing data have been produced suggesting that variations in appetite may result, at least in part, from the production of autoantibodies against appetite-regulating peptide hormones and neuropeptides [28]. If the presence of specific autoantibodies is also confirmed in anorexic weight-losing patients with cancer, this easily available procedure may contribute to the timely diagnosis of cancer anorexia– cachexia, particularly in its preclinical stages. However, the translation of the data obtained in experimental models into the clinical setting is limited and effective antianorexic and anticachexic therapies are lacking. To enhance our ability to treat the cancer anorexia– cachexia syndrome, it is likely that we should now focus our attention to the polymorphisms of specific genes [29], which in turn modulate the individual neurochemical/metabolic responses to tumor growth. This would

allow clinicians to predict the likelihood of developing anorexia and eventually cachexia, thereby permitting the use of preventive measures or at least the timely start of anticatabolic therapeutic strategies.

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