The role of hypothalamic inflammation, the hypothalamic-pituitary-adrenal axis and serotonin in the cancer anorexia-cachexia syndrome.

PURPOSE OF REVIEW: In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. RECENT FINDINGS: The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1ß-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. SUMMARY: Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.

Anorexic action of deoxynivalenol in hypothalamus and intestine.

Although deoxynivalenol (DON) suppresses food intake and subsequent weight gain, its contribution to anorexia mechanisms has not been fully clarified. Thus, we investigated the anorexic actions of DON in the hypothalamus and intestine, both organs related to appetite. When female B6C3F1 mice were orally exposed to different doses of DON, a drastic anorexic action was observed at a dose of 12.5 mg/kg body weight (bw) from 0 to 3 h after administration. Exposure to DON (12.5 mg/kg bw) for 3 h significantly increased the hypothalamic mRNA levels of anorexic pro-opiomelanocortin (POMC) and its downstream targets, including melanocortin 4 receptor, brain-derived neurotrophic factor, and tyrosine kinase receptor B; at the same time, orexigenic hormones were not affected. In addition, exposure to DON significantly elevated the hypothalamic mRNA levels of proinflammatory cytokines (IL-1ß, TNF-α, and IL-6) and activated nuclear factor-kappa B (NF-κB), an upstream factor of POMC. These results suggest that DON-induced proinflammatory cytokines increased the POMC level via NF-κB activation. Moreover, exposure to DON significantly enhanced the gastrointestinal mRNA levels of anorexic cholecystokinin (CCK) and transient receptor potential ankyrin-1 channel (TRPA1), a possible target of DON; these findings suggest that DON induced anorexic action by increasing CCK production via TRPA1. Taken together, these results suggest that DON induces anorexic POMC, perhaps via NF-κB activation, by increasing proinflammatory cytokines in the hypothalamus and brings about CCK production, possibly through increasing intestinal TRPA1 expression, leading to anorexic actions.

Long-term cysteine fortification impacts cysteine/glutathione homeostasis and food intake in ageing rats.

PURPOSE: Healthy ageing is associated with higher levels of glutathione. The study aimed to determine whether long-term dietary fortification with cysteine increases cysteine and glutathione pools, thus alleviating age-associated low-grade inflammation and resulting in global physiological benefits. METHODS: The effect of a 14-week dietary fortification with cysteine was studied in non-inflamed (NI, healthy at baseline) and in spontaneously age-related low-grade inflamed (LGI, prefrail at baseline) 21-month-old rats. Fifty-seven NI rats and 14 LGI rats received cysteine-supplemented diet (4.0 g/kg of free cysteine added to the standard diet containing 2.8 g/kg cysteine). Fifty-six NI rats and 16 LGI rats received a control alanine-supplemented diet. RESULTS: Cysteine fortification in NI rats increased free cysteine (P < 0.0001) and glutathione (P < 0.03) in the liver and the small intestine. In LGI rats, cysteine fortification increased total non-protein cysteine (P < 0.0007) and free cysteine (P < 0.03) in plasma, and free cysteine (P < 0.02) and glutathione (P < 0.01) in liver. Food intake decreased over time in alanine-fed rats (r² = 0.73, P = 0.0002), whereas it was constant in cysteine-fed rats (r² = 0.02, P = 0.68). Cysteine fortification did not affect inflammatory markers, mortality, body weight loss, or tissue masses. CONCLUSION: Doubling the dietary intake of cysteine in old rats increased cysteine and glutathione pools in selected tissues. Additionally, it alleviated the age-related decline in food intake. Further validation of these effects in the elderly population suffering from age-related anorexia would suggest a useful therapeutic approach to the problem.

Aquaporin-4 autoantibody: a neurogenic cause of anorexia and weight loss.

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease often associated with a highly specific autoantibody, aquaporin-4 antibody. Although the classic syndrome involves the optic nerves and spinal cord, aquaporin-4 antibody has been important in defining the true spectrum of NMO, which now includes brain lesions in areas of high aquaporin-4 expression. Brainstem involvement, specifically area postrema involvement in the medulla, has been associated with intractable vomiting in some patients with NMO. We describe a 14-year-old female with positive aquaporin-4 antibody whose clinical course was dominated by severe anorexia with associated weight loss (from 68-41kg; body mass index 25.2-15.6). Magnetic resonance imaging showed lesions in the medulla, pons, and thalami. Although she had asymptomatic radiological longitudinally extensive transverse myelitis, she never had symptoms or signs referable to the spinal cord or the optic nerves. We propose that anorexia and weight loss should be considered part of the NMO spectrum, probably related to area postrema involvement.

Glutamine-supplemented total parenteral nutrition improves immunological status in anorectic patients.

OBJECTIVE: Glutamine is an important substrate for critical cells of the immune system, in particular lymphocytes and macrophages, and it is considered a conditionally essential amino acid. Several studies have indicated that glutamine-enriched total parenteral nutrition improves immunologic status and shortens length of stay of critically ill patients. We investigated the effect of total parenteral nutrition supplemented with glutamine on the immune system in anorectic patients. METHODS: Thirty-six anorectic patients were randomized to receive standard parenteral nutrition or parenteral nutrition supplemented with glutamine 0.18 g kg(-1) d(-1) for 20 d. To evaluate the immune system status, we determined serum levels of neopterin and insulin growth factor-1 and lymphocyte count at baseline and after 10 and 20 d from the beginning of the therapy. RESULTS AND CONCLUSIONS: The results showed a significant increase of the serum levels of neopterin after 10 d of treatment with glutamine (26.44 +/- 3.08 versus 6.75 +/- 1.73 nmol/L, P < 0.001), thus proving a probable stimulating action carried out by glutamine on the immune system, as testified by the increase of lymphocytes.

Evidence for hypothalamic dysregulation in mouse models of anorexia as well as in humans.

Eating disorders constitute major medical health problems in the western world. Even though little is known about the molecular mechanisms behind abnormal eating behavior, it has become clear that the central nervous system (CNS), particularly the hypothalamus, plays a significant role. The anorexic anx/anx mouse is a unique model for studying food intake and energy expenditure. The anx mutation is linked to marked alterations in hypothalamic distributions of signal substances known to have potent regulatory roles in the control of food intake. Another mouse model that displays an anorectic phenotype similar to the anx/anx mouse is the Contactin KO mouse. This model displays very similar hypothalamic alterations as seen in the anx/anx mouse, arguing for a role of these specific hypothalamic changes in an anorectic phenotype. In human eating disorders, hypothalamic systems corresponding to those defective in mouse models could be compromised since autoantibodies against melanocortin peptides have been detected in anorectic and bulimic patients. These findings represent research avenues that may lead to a better understanding of eating disorders and development of targeted therapeutic approaches.

Comparative psychoneuroimmunology: evidence from the insects.

Interactions between immune systems, nervous systems, and behavior are well established in vertebrates. A comparative examination of these interactions in other animals will help us understand their evolution and present adaptive functions. Insects show immune-behavioral interactions similar to those seen in vertebrates, suggesting that many of them may have a highly conserved function. Activation of an immune response in insects results in illness-induced anorexia, behavioral fever, changes in reproductive behavior, and decreased learning ability in a broad range of species. Flight-or-fight behaviors result in a decline in disease resistance. In insects, illness-induced anorexia may enhance immunity. Stress-induced immunosuppression is probably due to physiological conflicts between the immune response and those of other physiological processes. Because insects occupy a wide range of ecological niches, they will be useful in examining how some immune-behavioral interactions are sculpted by an animal's behavioral ecology.

Current perspectives on behavioural and cellular mechanisms of illness anorexia.

Here we review our current understanding of the integration of immune, neural, metabolic and endocrine signals involved in the generation of anorexia during acute infection, with the focus on anorexia elicited by peripheral administration of bacterial lipopolysaccharide (LPS). We chose to limit this review to peripheral LPS-anorexia because the mechanisms underlying this response may also be valid for anorexia during other types of acute or chronic infections, with slight differences in the duration of anorexia, levels of circulating concentrations of pro-inflammatory cytokines and hypermetabolism. Evidence so far indicates that LPS-anorexia is a complex response beneficial to host defence that involves both peripheral and central action of pro-inflammatory cytokines, other immune factors, such as prostanoids, and neurotransmitters, such as serotonin. One interesting characteristic of LPS-anorexia is its sexual differentiation, an aspect mainly mediated by the gonadal hormone estradiol. Understanding the behavioural and molecular mechanisms of LPS-anorexia may even provide useful leads for identifying mechanisms of eating disorders in humans.

Circulating leptin mediates lipopolysaccharide-induced anorexia and fever in rats.

Anorexia and fever are important features of the host's response to inflammation that can be triggered by the bacterial endotoxin lipopolysaccharide (LPS) and the appetite suppressant leptin. Previous studies have demonstrated that LPS induces leptin synthesis and secretion in the periphery, and that the action of leptin on appetite suppression and fever are dependent on brain interleukin (IL)-1beta. However, the role of leptin as a neuroimmune mediator of LPS-induced inflammation has not been fully elucidated. To address this issue, we neutralized circulating leptin using a leptin antiserum (LAS) and determined how this neutralization affected LPS-induced anorexia, fever and hypothalamic IL-1beta. Adult male rats were separated into four treatment groups, namely LPS + normal sheep serum (NSS), LPS + LAS, saline + LAS and saline + NSS. Intraperitoneal injection of LPS (100 microg kg(-1)) induced a significant reduction in food intake and body weight, which were significantly reversed in the presence of LAS (1 ml kg(-1)), 8 and 24 h after treatment. In addition, LPS-induced fever was significantly attenuated by LAS over the duration of the fever response (8 h). Lipopolysaccharide induced an increase of circulating IL-6, another potential circulating pyrogen, which was not affected by neutralization of leptin at 2 h. Interleukin-1beta mRNA at 1 and 8 h, and IL-1 receptor antagonist (ra) at 2 h were significantly upregulated in the hypothalamus of LPS-treated animals. The induction of these cytokines was attenuated in the presence of LAS. These results are the first to demonstrate that leptin is a circulating mediator of LPS-induced anorexia and fever, probably through a hypothalamic IL-1beta-dependent mechanism.

Cancer anorexia: clinical implications, pathogenesis, and therapeutic strategies.

Anorexia and reduced food intake are important issues in the management of patients with cancer because they contribute to the development of malnutrition, increase morbidity and mortality, and impinge on quality of life. Accumulating evidence indicates that cancer anorexia is multifactorial in its pathogenesis, and most of the hypothalamic neuronal signalling pathways modulating energy intake are likely to be involved. Several factors are considered to be putative mediators of cancer anorexia, including hormones (eg, leptin), neuropeptides (eg, neuropeptide Y), cytokines (eg, interleukin 1 and 6, and tumour necrosis factor), and neurotransmitters (eg, serotonin and dopamine). These pathways are not isolated and distinct pathogenic mechanisms but are closely inter-related. However, convincing evidence suggests that cytokines have a vital role, triggering the complex neurochemical cascade which leads to the onset of cancer anorexia. Increased expression of cytokines during tumour growth prevents the hypothalamus from responding appropriately to peripheral signals, by persistently activating anorexigenic systems and inhibiting prophagic pathways. Hypothalamic monoaminergic neurotransmission may contribute to these effects. Thus, the optimum therapeutic approach to anorectic cancer patients should include changes in dietary habits, achieved via nutritional counselling, and drug therapy, aimed at interfering with cytokine expression or hypothalamic monoaminergic neurotransmission.

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production.

Anorexia and weight loss are frequent complications of acute and chronic infections and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. Selective attenuation of the hypophagic response to infection and maintenance of the production of factors essential for infection control would be a useful addition to antimicrobial therapy in the treatment of human disease. Here, we evaluate the relative contribution of cyclooxygenase (COX)-1- and COX-2-derived prostaglandins to anorexia and weight loss precipitated by systemic immune activation by lipopolysaccharide (LPS). Using COX isoform-selective pharmacological inhibitors and gene knockout mice, we found that COX-2 inhibition during LPS-induced inflammation results in preserved food intake and maintenance of body weight, whereas COX-1 inhibition results in augmented and prolonged weight loss. Regulation of neuropeptide Y, corticotropin-releasing hormone, leptin, and interleukin-6 does not change as a function of COX-2 inhibition after LPS administration. Our data implicate COX-2 inhibition as a therapeutic target to maintain nutritional status while still allowing a normal cytokine response during infection.

Dietary supplementation with conjugated linoleic acid does not improve nutritional status of tumor-bearing rats.

Tumor necrosis factor-alpha (TNF) is an immunoregulatory cytokine that plays a major role in tumor-induced anorexia and weight loss. Conjugated linoleic acids (CLA) are naturally occurring isomers of linoleic acid that, when added to the diet, improve food intake and body weight in mice injected with TNF. The purpose of the present study was to examine the effects of a diet supplemented with 0.5% CLA on the nutritional status of rats implanted with the Morris 7777 hepatoma. Body weight, food intake, serum levels of insulin-like growth factor, and splenocyte synthesis of TNF were not different in tumor-bearing animals fed CLA versus the control diet. However, insulin levels were increased in both tumor-bearing and control animals given CLA. The 0.5% CLA did not improve the nutritional status nor alter TNF synthesis in hypophagic tumor-bearing rats. The biological significance of increased insulin levels in animals given CLA remains to be determined.

[Effect of fuzheng jianpi recipe on content of trace element and immune function in children with spleen deficiency anorexia].

OBJECTIVE: To evaluate the efficacy and prospect of Fuzheng Jianpi Recipe (FZJPR) in treating children's Spleen deficiency anorexia (CSDA) by means of observing its effect on trace element content and immune function. METHODS: One hundred and thirty cases of CSDA were treated with FZJPR, one dose per day in decoction, orally taken, 30 days for one therapeutic course. Levels of T-lymphocyte subsets, IL-2R, immunoglobulin and trace elements were determined before and after treatment, and compared with those in the control group consisted of 60 healthy children. RESULTS: In the treated group, abnormal figures were shown in T-lymphocyte subsets, especially in lowering of CD3 and CD4 count before treatment, and IgG content was reduced also. After treatment, CD3, CD4, CD4/CD8 ratio as well as IgG and IgA were improved significantly (P < 0.01), IL-2R percentage approached normal. Moreover, the levels of Zn and Fe changed significantly (P < 0.01). CONCLUSION: FZJPR could improve the trace elements content and immune function in CSDA children, so it is effective in treating CSDA.

Psychomotor retardation, anorexia, weight loss, sleep disturbances, and loss of energy: psychopathological correlates of hyperhaptoglobinemia during major depression.

Recently, we have established that major depression is characterized by hyperhaptoglobinemia, which may be regarded as an index of an "acute" phase response in that illness. The present study investigates the psychopathological correlates of increased plasma concentrations of haptoglobin (Hp) in major depression. To this end, the authors studied the Hp levels in relation to depressive items of the Structured Clinical Interview for DSM-III (SCID) and the Hamilton Rating Scale for Depression (HRSD) in 90 depressed subjects. There was a significant positive relationship between the SCID symptoms anorexia/weight loss, sleep, and psychomotor disorders and Hp plasma concentrations. Hp plasma levels were significantly and positively correlated with overall severity of illness (HRSD). The HRSD symptom correlates of higher Hp levels were loss of interest, middle insomnia, and psychomotor retardation. Up to 31.4% of the variance in Hp plasma values could be explained by psychomotor disorders, anorexia, weight loss, middle insomnia, and less diurnal variation of mood. It is suggested that hyperhaptoglobinemia, as an index of an "acute" phase response in major depression, is related to the somatic dimension of depressive illness.