Elsevier

Nutrition

Volume 17, Issues 7–8, July–August 2001, Pages 664-668
Nutrition

Workshop: anorexia during disease—from research to clinical practice
How the immune and nervous systems interact during disease-associated anorexia

https://doi.org/10.1016/S0899-9007(01)00602-5Get rights and content

Abstract

Anorexia is one of the most common symptoms associated with illness and constitutes an adaptive strategy in fighting acute infectious diseases. However, prolonged reduction in food intake and an increase in metabolic rate, as seen in the anorexia-cachexia syndrome, lead to depletion of body fat and protein reserves, thus worsening the organism’s condition. Because the central nervous system controls many aspects of food intake, soluble factors known as cytokines that are secreted by immune cells might act on the brain to induce anorexia during disease. This review focuses on the communication pathways from the immune system to the brain that might mediate anorexia during disease. The vagus nerve is a rapid route of communication from the immune system to the brain, as subdiaphragmatic vagotomy attenuates the decrease in food-motivated behavior and c-Fos expression in the central nervous system in response to peripheral administration of the proinflammatory cytokine, interleukin-1β, or bacterial lipopolysaccharide. At later time points after peripheral lipopolysaccharide administration, interleukin-1 itself acts in the brain to mediate anorexia and is found in the arcuate nucleus of the hypothalamus. The mechanisms by which interleukin-1β gains access to the brain and the potential role of neuropeptide-Y-containing neurons in the arcuate hypothalamus in mediating anorexia during disease are discussed.

Introduction

Anorexia is one of the most common symptoms associated with illness. The suppression of food intake is seen in humans and many animals with a variety of systemic diseases and more localized infections.1 Anorexia might, therefore, constitute an adaptive strategy in fighting infectious diseases.1 By decreasing their food intakes, animals reduce the chance of raising plasma concentrations of free iron, which is an essential element that many bacteria need to replicate.2 Low iron levels alone do not impair bacterial growth, but proliferation of bacteria is inhibited when iron levels are low and body temperature is elevated.3 This is probably due to decreased bacterial synthesis of iron-chelating compounds at temperatures above 37°C.4 Therefore, anorexia and fever might limit bacterial proliferation.

The low incidence of infection in iron-deficient humans is in accordance with this hypothesis. In 1978 Murray et al. reported a five-fold increase in the incidence of infectious episodes after treatment of iron-deficient nomads with iron.5 Based on that finding and their experience with famines in Africa, they proposed that therapeutic refeeding during infection can be harmful.6 When that hypothesis was tested experimentally, forced feeding of mice during acute bacterial infection reduced survival time and increased mortality,7 whereas food deprivation increased survival.8 Altogether, these findings indicate that anorexia after acute infection is an adaptive response.

Interestingly, Murray et al. proposed an additional mechanism by which reduced food intake might benefit host survival after infection. Anorexia would lead to premature death of infected cells and thus prevent infection of other cells. Recent findings showing that food restriction induces apoptosis in the liver9 and that apoptosis constitutes a defense mechanism against neoplasic cells and intracellular and some extracellular pathogens are in accordance with that hypothesis.10 It remains to be shown, however, whether apoptosis is enhanced as a consequence of anorexia during disease.11

Although anorexia constitutes a defense strategy against acute infections, a prolonged reduction in food intake and an increase in metabolic rate will deplete body fat and protein reserves, thus worsening the organism’s condition.12 This so-called anorexia-cachexia syndrome occurs in almost two-thirds of patients with advanced cancer and has been estimated to account for 10% to 22% of cancer deaths.13, 14 In view of the adaptive value of anorexia and fever during acute infectious disease, the anorexia-cachexia syndrome in late-stage cancer patients may be interpreted as the spillover of those defense mechanisms.

Section snippets

Anorexia during disease occurs independent of fever and changes in locomotor activity

Anorexia during disease has long been thought to be the consequence of fever or the result of a general weakness of the sick individual. However, hyperthermia alone does not suppress food intake,15 indicating that anorexia during disease is not a necessary consequence of fever. Because muscle weakness and pain are common symptoms of infectious diseases,1 anorexia during disease might be due to difficulty in or pain interfering with hoarding or chewing of food. Hoarding of food requires high

Interleukin-1 acts rapidly on vagus nerves to activate the central nervous system during disease

The central nervous system (CNS) controls many aspects of food intake and energy homeostasis.17 Soluble factors secreted by immune cells are, therefore, proposed to act on the nervous system to induce anorexia during disease.1 One of the soluble factors secreted by tissue macrophages after detection of bacterial LPS is the proinflammatory cytokine interleukin-1β (IL-1β). Intraperitoneal administration of IL-1β induces a reduction in total caloric intake and a relative increase in carbohydrate

Conclusions

The work reviewed indicates that anorexia during acute inflammation is an adaptive response that is probably due to an altered motivation to eat. Peripheral administration of IL-1β, one of the proinflammatory cytokines released by tissue macrophages after infection, mimics the anorectic effects of bacterial LPS and so is thought to be an important mediator of anorexia during disease. The vagus nerve constitutes a rapid route of communication between the immune system and the brain because

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    The work described was supported by European Community grants BIOMED 2 CT97-2492 and TMR CT97-0149.

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