Role Infection in Anorexia: Mechanism and Immunopathophysiology

Anorexia is part of the body’s acute-phase response to illness. Whereas anorexia is a common behavioral response to infectious diseases, the reasons for and mechanisms behind this observation are still unknown. The anorexia of infection is part of the host’s acute phase response (APR). Despite being beneficial in the beginning, long lasting anorexia delays recovery and is ultimately deleterious.

When it is considered on an evolutionary basis, the organism must have net benefits from anorexia. The first response to infection is the development of acute phase response (APR). The APR is triggered by microbial products and characterized by production of several cytokines known to induce anorexia. Microbial products such as bacterial cell wall compounds (e.g., lipopolysaccharides and peptidoglycans), microbial nucleic acids (e. g., bacterial DNA and viral double-stranded RNA), and viral glycoproteins trigger the APR and presumably also the anorexia during infections. Microbial products stimulate the production of proinflammatory cytokines (e.g., interleukins [ILs], tumor necrosis factor-alpha, interferons), which serve as endogenous mediators. Several microbial products and cytokines reduce food intake after parenteral administration, suggesting a role of these substances in the anorexia during infection. Microbial products are mainly released and cytokines are produced in the periphery during most infections; they might inhibit feeding through neural and humoral pathways activated by their peripheral actions.

Role Interleukins and tumor necrosis factor

Cytokines, such as interleukins and tumor necrosis factor-alpha (TNFalpha), are produced in response to immune stimulation and have systemic effects, mediated by the central nervous system (CNS). Interleukins, in particular interleukin [IL]-1beta, and TNFalpha reduce food intake after peripheral and central administration, suggesting that they contribute to the anorexia during various infectious, neoplastic and autoimmune diseases.

Because cytokines are mainly produced in the periphery during most of these diseases, IL-1beta and TNFalpha may inhibit feeding indirectly through neural and humoral pathways activated by their peripheral actions. Activation of afferent nerve fibers by locally produced cytokines in the periphery is involved in several cytokine effects, but is not crucial for the anorectic effect of systemic immune stimulation. Cytokines increase OB protein (leptin) expression in the adipose tissue, and leptin may contribute to, but is also not essential for, the anorectic effects of cytokines. Finally, circulating IL-1beta and TNFalpha may act directly on the brain or cytokine synthesis in the brain may contribute to the anorectic effect of systemic immune stimulation.

Central mediators of the anorectic effects of cytokines appear to be neurochemicals involved in the normal control of feeding, such as serotonin, corticotropin releasing factor, histamine, alpha-melanocyte stimulating hormone, and neuropeptide Y. The well-documented cytokine production in the gut in relation to feeding and the expression of TNFalpha by adipocytes suggest that IL-1beta and TNFalpha may also play a role in the control of normal feeding and energy balance. All in all, reciprocal, synergistic and antagonistic interactions between various pleiotropic cytokines and between cytokines and neurochemicals form a complex network that mediates the effects of cytokines on feeding and energy balance.

Several microbial products and cytokines reduce food intake after parenteral administration, suggesting a role of these substances in the anorexia during infection. Locally released cytokines may inhibit feeding by activating peripheral sensory fibers directly or indirectly, and without a concomitant increase in circulating cytokines. However, the final center for appetite or eating is the central nervous system (CNS). Thus, these peripheral signals must reach and interact with brain regions that control appetite. In addition, a direct action of cytokines and microbial products on the CNS is presumably involved in the anorexia during infection.

Activation of peripheral afferents by locally produced cytokines is involved in several cytokine effects, but is not crucial for the anorectic effect of microbial products and IL-1beta. Cytokines increase leptin expression in the adipose tissue, and leptin may contribute to, but is also not essential for, the anorectic effects of microbial products and cytokines. In addition, a direct action of cytokines and microbial products on the central nervous system (CNS) is presumably involved in the anorexia during infection. Cytokines can reach CNS receptors through circumventricular organs and through active or passive transport mechanisms or they can act through receptors on endothelial cells of the brain vasculature and stimulate the release of subsequent mediators such as eicosanoids. De novo CNS cytokine synthesis occurs in response to peripheral infections, but its role in the accompanying anorexia is still open to discussion. Central mediators of the anorexia during infection appear to be neurochemicals involved in the normal control of feeding, such as serotonin, dopamine, histamine, corticotropin releasing factor, neuropeptide Y, and alpha-melanocyte-stimulating hormone. Reciprocal, synergistic, and antagonistic interactions between various pleiotropic cytokines, and between cytokines and neurochemicals, form a complex network that mediates the anorexia during infection. Current knowledge on the mechanisms involved suggests some therapeutic options for treatment. Substances that block common key steps in cytokine synthesis or cytokine action, or inhibitors of eicosanoid synthesis, may hold more promise than attempts to antagonize specific cytokines. To target the neurochemical mediation of the anorexia during infection may be even more efficient.

Future research should address these neurochemical mechanisms and the cytokine actions at the blood-brain barrier. Further unanswered questions concern the modulation of the anorexia during infection by gender and nutritional state.

Bacterial Lipopolysaccharides and Cytokines

The immune signalling pathways of LPS-induced, and presumably acute illness-induced, anorexia converge on central neural signalling systems that control food intake and energy balance in healthy individuals.

Bacterial lipopolysaccharide (LPS) and other microbial substances trigger the organism’s acute phase response and cause acute illness anorexia. Pro-inflammatory cytokines are major endogenous mediators of acute illness anorexia, but how LPS or cytokines stimulate the brain to inhibit eating is not fully resolved. Microbial products such as lipopolysaccharides (LPS), which are also commonly used to model acute illness, trigger the acute-phase response and cause anorexia mainly through pro-inflammatory cytokines.

LPS stimulate cytokine production through the cell-surface structural molecule CD14 and toll-like receptor-4. Cytokines ultimately change neural activity in brain areas controlling food intake and energy balance. The blood-brain barrier endothelial cells (BBB EC) are an important site of cytokine action in this context. BBB EC and perivascular cells (microglia and macrophages) form a complex regulatory interface that modulates neuronal activity by the release of messengers (e.g. PG, NO) in response to peripheral challenges. Serotonergic neurons originating in the raphe nuclei and glucagon-like peptide-1-expressing neurons in the hindbrain may be among the targets of these messengers, because serotonin (5-HT), acting through the 5-HT2C receptor, and glucagon-like peptide-1 have recently emerged as neurochemical mediators of LPS anorexia.

The central melanocortin system, which is a downstream target of serotonergic neurons, also appears to be involved in mediation of LPS anorexia. Interestingly, LPS also reduce orexin expression and the activity of orexin neurons in the lateral hypothalamic area of fasted mice. As the eating-stimulatory properties of orexin are apparently related to arousal, the inhibitory effect of LPS on orexin neurons might be involved in LPS-induced inactivity and anorexia.

One emerging mechanism involves the activation of the enzyme cyclooxygenase-2 (COX-2) in blood-brain barrier endothelial cells and the subsequent release of prostaglandin E2 (PGE2). Serotonin neurons in the midbrain raphe are targets of PGE2, and serotonergic projections from the midbrain raphe to the hypothalamus appear to be crucial for LPS anorexia. That is, raphe projections activate the corticotrophin-releasing hormone neurons in the paraventricular nucleus which then elicit the stress response and the pro-opiomelanocortin neurons in the arcuate nucleus which then release alphaMSH and elicit anorexia. Here we review available data to support a role for this brain mechanism in acute illness anorexia by center staging PGE2 signaling pathways that converge on central neural circuits that control normal eating. In addition, we review interactions between gonadal hormones and immune function that lead to sex differences in acute illness anorexia. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB].

PGE2 and LPS-induced anorexia

Anorexia is an element of the acute-phase immune response. Its mechanisms remain poorly understood. Activation of inducible cyclooxygenase-2 (COX-2) in blood-brain-barrier endothelial cells and subsequent release of prostaglandins (e.g., prostaglandin E2, PGE2) may be involved. Therefore, we sought to relate the effects of prostaglandins on the anorexia following gram-negative bacterial lipopolysaccharide treatment (LPS) to neural activity in the dorsal and median raphe nuclei (DRN and MnR) in rats. COX-2 antagonist (NS-398, 10mg/kg; IP) administration prior to LPS (100μg/kg; IP) prevented anorexia and reduced c-Fos expression the DRN, MnR, nucleus tractus solitarii and several related forebrain areas. These data indicate that COX-2-mediated prostaglandin synthesis is necessary for LPS anorexia and much of the initial LPS-induced neural activation. Injection of NS-398 into the DRN and MnR (1ng/site) attenuated LPS-induced anorexia to nearly the same extent as IP NS-398, suggesting that prostaglandin signaling in these areas is necessary for LPS anorexia. Because the DRN and MnR are sources of major serotonergic projections to the forebrain, these data suggest that serotonergic neurons originating in the midbrain raphe play an important role in acute-phase response anorexia.

Serotonin and LPS anorexia.

LPS, a potent activator of the innate immune system, is commonly used to investigate the acute phase response to infection, including anorexia. Serotonin 2C-receptor signaling has been shown to be involved in the mediation of LPS anorexia. Here we used the selective, potent and brain-penetrant serotonin 2C-receptor antagonist SB 242084 to identify the brain sites involved in LPS anorexia.

Male Long-Evans rats received 1 ml/kg intraperitoneal injections of 0 or 0.3 mg/kg SB 242084 and intraperitoneal injections of 0 or 100 microg/kg LPS 1 h later, at dark onset. Food intake was measured in one set of rats and c-Fos immunoreactivity in another, unfed, group 90 min after LPS injection. SB 242084 markedly attenuated the LPS-induced reduction in food intake, with no anorexia evident for the first 2 h after LPS. SB 242084 also completely blocked the LPS-induced increases in c-Fos expression in the paraventricular nucleus, central nucleus of the amygdala, nucleus tractus solitarii, median raphe nucleus and dorsal raphe nucleus and partially blocked it in the A1 noradrenergic area of the ventrolateral medulla and the raphe pallidus nucleus. SB 242084 did not significantly alter the c-Fos response in the arcuate nucleus or the raphe magnus nucleus.

These data indicate that 2C receptor signaling activates a diffuse neural network, presumably mediating anorexia and other responses to LPS; they also suggest that the arcuate and the raphe magnus neurons that express c-Fos after LPS are not necessary for LPS anorexia.

von Meyenburg C, et al. Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-, and leptin-induced anorexia. Pharmacol Biochem Behav. 2003 Mar;74(4):1025-31.

Mayenburg observe the role of serotonin (5-HT) and the 5-HT(1A) and 5-HT(2C) receptors in the anorectic effects of centrally administered lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), and leptin. Food intake was measured in rats after intracerebroventricular (ICV) injections of LPS (20 ng), IL-1 beta (10 ng), or leptin (1 microg) at lights out, followed by intraperitoneal (IP) injections of either the 5-HT(1A) autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) (125 microg/kg) or the 5-HT(2C) receptor antagonist SB 242084 (0.3 mg/kg) at the onset of anorexia.

SB 242084 significantly attenuated the food intake reduction caused by all compounds (all P<.01). IP 8-OH-DPAT attenuated ICV IL-1 beta-induced anorexia (P<.01). The study also tested the involvement of the median raphe 5-HT(1A) receptors in peripheral LPS- and IL-1 beta-induced anorexia. Rats were injected intraperitoneally with either LPS (100 microg/kg) or IL-1 beta (2 microg/kg) at lights out, and 8-OH-DPAT (4 nmol) was administered directly into the median raphe nucleus at the onset of anorexia. Median raphe injections of 8-OH-DPAT significantly attenuated both IL-1 beta- and LPS-induced anorexia (both P<.01).

These results implicate the 5-HT(2C) receptors in the mediation of central LPS-, IL-1 beta-, and leptin-induced anorexia. The study also suggest that the midbrain raphe nuclei play a role in mediating the anorectic response to peripheral LPS and IL-1 beta.

Rats consistently reduce their food intake following injection of bacterial lipopolysaccharides (LPS). Because LPS increases CNS serotonin (5-HT) turnover, and because increases in CNS 5-HT turnover are associated with a decrease in food intake. Hrupka BJ conducted a series of studies to examine 5-HT’s potential role in LPS-induced anorexia. Chronic CNS 5-HT depletion by cisterna magna (CM) administration of 5,7-dihydroxytryptamine (5,7-DHT) failed to attenuate LPS-induced (100 microg/kg, ip) anorexia.

In subsequent experiments, LPS was injected at lights out (hour 0) and [8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT)] or N-CBZ-[(8beta)-1,6-dimethylergolin-8-yl]methylamine (metergoline) was injected at hour 5 – the time when LPS-treated rats become anorectic. Food intake was measured during the subsequent 2 h. In LPS-treated rats, 8-OH-DPAT (62.5, 125, or 250 microg/kg, sc) injection increased food intake. In a 2 x 2 factorial arrangement of LPS and 8-OH-DPAT, 125 microg/kg 8-OH-DPAT increased food intake significantly more in LPS-treated rats than in non-LPS-treated rats (significant LPS x 8-OH-DPAT interaction). In LPS-treated rats, 1 and 5 mg/kg metergoline significantly enhanced food intake.

However, in a 2 x 2 arrangement of LPS and metergoline, 1 mg/kg metergoline failed to increase food intake in LPS and non-LPS-treated rats in two separate trials. The ability of the 5-HT(1A) receptor agonist 8-OH-DPAT to attenuate LPS-induced anorexia in rats supports a role of 5-HT in LPS-induced anorexia.

References

  • Kanra GY, et al. Infection and anorexia.Turk J Pediatr. 2006 Oct-Dec;48(4):279-87.
  • Langhans W. Anorexia of infection: current prospects. Nutrition. 2000 Oct;16(10):996-1005.
  • Langhans W. Signals generating anorexia during acute illness. Proc Nutr Soc. 2007 Aug;66(3):321-30.
  • Asarian L.A new look on brain mechanisms of acute illness anorexia. Physiol Behav. 2010 Jul 14;100(5):464-71
  • Kopf BS, et al. Evidence that PGE2 in the dorsal and median raphe nuclei is involved in LPS-induced anorexia in rats. Pharmacol Biochem Behav. 2011 Sep;99(3):437-43. Epub 2011 Apr 17.
  • Hrupka BJ, et al. A role for serotonin in lipopolysaccharide-induced anorexia in rats. Pharmacol Biochem Behav. 2001 Feb;68(2):355-62.
  • Kopf BS, et al.Serotonin 2C receptor signaling in a diffuse neuronal network is necessary for LPS anorexia. Brain Res. 2010 Jan 8;1306:77-84.
  • von Meyenburg C, et al. Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-, and leptin-induced anorexia. Pharmacol Biochem Behav. 2003 Mar;74(4):1025-31.
  • Langhans W, et al. Interleukins and tumor necrosis factor as inhibitors of food intake. Neuropeptides. 1999 Oct;33(5):415-24.

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