Cachexia and neuropeptide Y

Nutrition 24 (2008) 815– 819 www.elsevier.com/locate/nut

Cachexia and neuropeptide Y John E. Morley, M.B., B.Ch.a,*, and Susan A. Farr, Ph.D.b a

Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA b VA Medical Center, St. Louis, Missouri, USA Manuscript received and accepted June 15, 2008.

Abstract

Cachexia or wasting disease occurs commonly in diseases that have an overproduction of proinflammatory cytokines associated with them. The hallmarks of cachexia are loss of lean and adipose tissue, anorexia, anemia, memory disturbance, and sickness behavior. This review suggests that increased inducible nitric oxide synthase production in the hypothalamus leads to severe anorexia and that this is the pathway through which proinflammatory cytokines produce anorexia. Orexigenic peptides, such as neuropeptide, ghrelin, and orexin A, and anorectic peptides, such as leptin, produce their effects through neuronal nitric oxide synthase. Activation of neuronal nitric oxide synthase results in increased adenosine monophosphate kinase and a decrease in malonyl coenzyme A, leading to increased food intake. © 2008 Elsevier Inc. All rights reserved.

Keywords:

Cachexia; Peptides; Inflammatory

Introduction Cachexia occurs in response to excessive inflammation (proinflammatory cytokine release) [1–3]. It leads to severe weight loss. Weight loss occurs equally from muscle and fat. Anorexia and sickness behavior are features of cachexia. Cachexia is associated with anemia, hypertriglyceridemia, insulin resistance, elevated acute-phase proteins such as C-reactive protein, hypoalbuminemia, and decreased intestinal activity. Other causes of weight loss besides cachexia are poor nutritional intake (food shortage or anorexia), malabsorption, sarcopenia, hypermetabolism, and dehydration [4]. Table 1 compares the different causes of weight loss. Weight loss and low body mass index are poor prognostic signs being associated with a doubling in mortality risk [5,6]. Weight loss is a key element of the frailty syndrome [7–9]. Malnutrition is commonly associated with a variety of diseases, e.g., in 30% of patients with renal failure, 10% of those with chronic obstructive pulmonary disease, 15% of those with congestive heart failure, ⬎50% of those with endstage acquired immunodeficiency syndrome, and 15–70% of those with cancer (dependent on the type of cancer) [2].

* Corresponding author. Tel.: ⫹314-577-8462; fax: ⫹314-771-8575. E-mail address: [email protected] (J. E. Morley). 0899-9007/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2008.06.020

Anorexia independently predicts mortality with a hazard ratio of 2.9 (95% confidence interval 1.1–7.4) [10]. For this reason we independently developed the Simplified Nutrition Assessment Questionnaire. This questionnaire is highly predictive of future weight loss [11]. Several reasons have been suggested for the deleterious causes of weight loss [6]. Protein– energy malnutrition leads to immune dysregulation including low levels of CD4⫹ T cells, infections, pressure ulcers, anemia, loss of bone and subsequent hip fractures, muscle loss, and functional decline. Weight loss may be a harbinger of an occult disease such as cancer. Lipolysis leads to increased circulating lipids and, in particular, an increase in small dense low-density lipoproteins. Loss of fat results in the release of fat-soluble toxins, such as insecticides, that have accumulated in the adipose tissue over many years, the so-called poisonous infusion. There can be altered effects of fat-soluble drugs and those that are albumin bound, leading to adverse medication effects.

Anorexia and sarcopenia Anorexia occurs physiologically with aging, with food intake declining by one-third in men and 25% in women over the lifespan [12]. The major causes of this decline are

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Table 1 Comparison of the different kinds of weight loss

Weight loss Lean tissue Fat tissue Appetite Anemia Proteolysis C-reactive protein Vitamin A Albumin

Cachexia

Anorexia/starvation

Malabsorption

Sarcopenia

Hypermetabolism

Severe Decreased Decreased Decreased Yes Yes Increased Normal Decreased

Moderate Decreased Decreased Decreased Mild No Normal Normal Mild decrease

Moderate Decreased Decreased Increased Mild No Normal Decreased Mild decrease

Mild Decreased Increased Unchanged No Yes Normal Normal Normal

Moderate Decreased Decreased Increased No Yes Normal Normal Normal

alterations in taste and smell, decreased rate of gastric emptying, elevated cholecystokinin levels, and a decline in testosterone leading to an increase in leptin levels in men. There is evidence that a decline in neuropeptide Y (NPY) levels and function in the central nervous system and a decrease in nitric oxide activity play a key role in the central nervous system in producing this anorexia of aging [13–15]. Dronabinol (a synthetic tetrahydrocannabinol) increases food intake in anorectic and cachectic persons [16]. Cannabinoids increase NPY release in the hypothalamus, suggesting a potential mechanism by which the orexigenic activity is produced [17]. The major causes of pathologic weight loss are depression, medications, infections, and cancer [18,19]. Sarcopenia is the age-associated loss of muscle mass. It is generally defined as being below 2 standard deviations of the appendicular lean mass divided by height squared of a normal young population. With aging, loss of muscle mass does not directly correlate with loss of strength. This is due to the infiltration of fat into muscle of individuals as they age. Our studies have shown that persons with obese sarcopenia or “fat frail” are at extremely high risk of developing future disability and mortality [20]. Fat infiltration into muscle can be detected by attenuation of the signal when muscle mass is measured with computed tomography. In this case, the condition is referred to as myosteatosis. There are multiple causes of sarcopenia. Genetic predisposition (such as myostatin, angiotensin converting enzyme, insulin-like growth factor-2, and ciliary neurotrophic factor genotypes) and birth weight are predictors of sarcopenia developing in old age [5]. Vitamin D deficiency and a decline in testosterone levels play a role in the development of sarcopenia. The role of growth hormone and insulin-like growth factor-1 is less certain, with evidence suggesting that the age-related decline leads to a loss of mass but has little effect on strength. Low-grade increases in proinflammatory cytokines, e.g., tumor necrosis factor-␣ and interleukin-6, have been implicated in the pathogenesis of sarcopenia. A decline in motor units results in decreased muscle efficiency. This appears to be related to the decline in ciliary neurotrophic factor that occurs with aging. Insulin resistance plays a role in the development of sarcopenia and this is closely related to age-related mitochondrial abnormali-

ties. Atherosclerosis leads to muscle hypoxia and loss of muscle. Myostatin overactivity may lead to a decline in satellite (repair) cells. Overwhelmingly, the major cause of sarcopenia is physical inactivity.

Cachexia Proinflammatory cytokines result in activation of the ubiquitin-proteasome system, which leads to degradation of proteins [1,2]. These amino acids are then available to produce acute-phase proteins such as serum amyloid protein and C-reactive protein. Cytokines inhibit albumin production but, more importantly, result in leakage of cytokines from the blood into the intracellular space. This combination leads to marked hypoalbuminemia. Thus, low albumin and prealbumin levels represent a sign of cytokine excess rather than nutritional depletion [3]. Lipolysis leads to an increase in triacylglycerols and free fatty acids. Cytokines decrease the rate of gastric emptying and slow intestinal motility. Cytokines directly produce anorexia, sickness behavior, and impaired memory. Sickness behavior results in decreased voluntary energy utilization. Cytokines also lead to hypercortisolemia and an increase in circulating epinephrine. Cytokines result in hepcidin production and thus the anemia of chronic disease. Biochemically cytokines activate MURF-I, which activates the ubiquitin-proteasome system. In addition, through nuclear factor-␬B, they activate caspase-8, leading to DNA fragmentation and apoptosis. Cytokines also inhibit cell cycling, thus decreasing the production of new satellite cells. One of the few compounds to produce weight gain in cachexia is megestrol acetate. Megestrol acetate is a mixed progestogenic corticosteroid with mild anabolic action. Megestrol acetate decreases proinflammatory cytokine release. In addition, its orexigenic effect appears to be due to activation of NPY in the arcuate, lateral hypothalamus, dorsomedial hypothalamus, and medial preoptic area [20]. Corticosteroids have been used since the 1950s to treat arthritis and the associated muscle wasting that occurs. Anabolic steroids increase muscle mass and, in high

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Chemotherapy

ANOREXIA-CACHEXIA SYNDROME IN CANCER Central Mechanisms

Conditioned Food Aversion

Melanocortin

Depression Prostaglandins

NPY Serotonin

Tryptophan

CRF

ACTH CYTOKINES

Dynorphin

ANOREXIA

Cortisol ZINC

Tumor

Urine Zinc

CNTF

Fig. 1. Central factors involved in the cancer anorexia– cachexia syndrome. ACTH, adreno corticotrophin hormone; CNTF, ciliary neurotrophic factor; CRF, corticotrophin-releasing factor; NPY, neuropeptide Y.

doses, muscle power. They appear to be more effective when coupled with high-protein supplements. Selective androgen receptor molecules tend to have specific effects on muscle. Ostarine, a selective androgen receptor molecule, increases fat-free mass and stair-climbing power. There is some evidence that anti-myostatin antibodies may be useful in treating cachexia. The prototypic cachexia syndrome is the anorexia– cachexia syndrome in cancer [21]. Cancer has a variety of peripheral effects that lead to loss of fat and muscle. Tumors also have multiple central mechanisms that lead to anorexia (Fig. 1). Chemotherapy can lead to conditioned food aversion and anorexia. Depression plays a major role in the anorexia– cachexia syndrome. Tumors are often associated with a marked loss of urinary zinc, which leads to a decline in the ␬-opioid-dymorphin feeding drive. Elevated circulating tryptophan levels activate hypothalamic serotonin, which drives the production of corticotrophin-releasing factor (CRF). CRF is a potent anorectic agent. Elevated prostaglandins and melanocortin result in a decline in NPY [22].

Nitric oxide, NPY, and cachexia Nitric oxide antagonism has been demonstrated to inhibit food intake [23]. This effect is reversed by Larginine. Chronic antagonism of nitric oxide produces weight loss in mice [24]. Nitric oxide antagonism reverses the orexigenic effect of NPY. Genetically obese mice (ob/ob) have elevated levels of nitric oxide synthase (NOS) and its messenger RNA [25]. Long-term administration of a NOS antagonist causes weight loss in obese (ob/ob) and diabetic mice [26]. The major effect of inhibition of NOS inhibition appears to be to decrease the motivation to eat [27]. Inhibition of NOS leads to increased hypothalamic serotonin turnover [28].

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Ghrelin is a peptide hormone produced from the fundus of the stomach. It increases feeding, improves memory, and produces growth hormone release from the stomach [29,30]. Ghrelin increases food intake and handgrip strength in persons with cardiac cachexia [16]. Ghrelin produces its effect on feeding and on growth hormone secretion through NOS activation [29]. Orexin A is a potent orexigenic peptide that exerts its effect in the hypothalamus. Orexin A increases NOS and its feeding effect is blocked by inhibition of NOS [31]. Orexin A fails to increase feeding in neuronal NOS (nNOS) knockout mice. The NPY Y1 receptor is colocalized with NOS in the hypothalamus [22]. Kittner et al. [32] found that the P2Y1 receptor and nNOS coexist in ventromedial hypothalamus neurons. The feeding effect of the P2Y1 receptor was mediated through nitric oxide– cyclic guanosine monophosphate. NPY increased NOS by 42% in the hypothalamus of CD-1 mice [33]. In contrast, NPY effects on memory are mediated by the Y2 receptor [34]. Leptin given for 3 d to obese mice (ob/ob) decreased food intake and decreased NOS by 32% [33]. While inhibiting nNOS, leptin increased serotonin, supporting the interaction between nitric oxide and serotonin [35]. Further evidence for the importance of NOS in the feeding effects of peptides is the fact that NPY and ghrelin fail to increase food intake in nNOS knockout mice. In tumor-bearing mice inducible NOS (iNOS) and nNOS were significantly increased in the paraventricular nucleus and lateral hypothalamic area [36]. These changes in iNOS were different from those seen in pairfed animals, suggesting a role for iNOS in cancer cachexia. This is further supported by the fact that iNOS but not nNOS is increased in the hypothalamus in response to tumor necrosis factor-␣ [34]. The effect of tumor necrosis factor is blocked in iNOS knockouts, but not in nNOS knockouts. Our preliminary data suggest that the potent anorectic, CRF, increases NOS activity. These findings suggest that cytokine-induced anorexia may be mediated through an iNOS–CRF pathway. This suggests a ying-yang effect of nitric oxide on feeding, with nNOS mediating orexigenic effects and iNOS mediating the anorectic effects. The biochemical mechanism by which nNOS modulates feeding appears to involve activation of adenosine monophosphate (AMP) kinase. Activated AMP kinase increases food intake and has been shown to be a pathway that is responsible for NPY and leptin effects on feeding [37–39]. AMP kinase lowers malonyl coenzyme A (CoA) levels in the hypothalamus by phosphorylating/inhibiting acetyl CoA carboxylase. This leads to a decrease in the levels of malonyl-6A in the hypothalamus [38]. Levels of malonyl-6A in the hypothalamus alter with fasting and feeding [36]. Inhibition of fatty acid synthesis leads to an increase in malonyl CoA, accompanied by suppression of food intake and profound weight loss. Viral vectors that overexpress malonyl CoA decarboxyl-

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References

Fig. 2. Role of NOS in the regulation of feeding and cachexia. AMP, adenosine monophosphate; CCK, cholecystokinin; CoA, coenzyme A; CRF, corticotrophin-releasing factor; iNOS, inducible nitric oxide synthase; nNOS, neuronal nitric oxide synthase; NPY, neuropeptide Y; TNF␣, tumor necrosis factor-␣.

ase lower malonyl CoA levels and lead to increased food intake. An overview of the regulation of food intake in the hypothalamus is shown in Figure 2.

Conclusion Cachexia is a common condition that occurs in response to an excessive inflammatory response to a variety of diseases. It involves the loss of muscle and fat and is associated with anorexia. It needs to be distinguished from other causes of weight loss such as anorexia/starvation, malabsorption, sarcopenia, hypermetabolism, and dehydration. In this review we have put forward the hypothesis that the anorexia of cancer is mediated through nitric oxide. Excess proinflammatory cytokines lead to an increase in CRF with activation of iNOS leading to an increased malonyl CoA and severe weight loss. The orexigenic effects of orexigenic peptides, such as NPY, and anorectic agents, such as leptin, are mediated through nNOS, which activate AMP kinase resulting in a decrease in malonyl CoA and increased feeding.

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