Cachexia in experimental models

Cachexia refers to a state of severe malnutrition characterized by anorexia, weight loss, and muscle wasting. Although it is most commonly considered in the context of cancer, it may occur as a consequence of a variety of chronic diseases. Cachexia appears to differ from “semistarvation” in that there is evidence of metabolic changes that are different from the normal response to reduced food intake. Animal models are useful in the study of cachexia because they allow homogeneous groups of subjects, free from confounding influences, to be studied. Accurate control of diet is possible, and pair-fed controls can be used to allow specific investigation of the metabolic component. However, the model must show features that are appropriate for the disease being studied. In the case of cancer this means using a model in which cachexia occurs without too high a tumor burden or growth rate or too severe a reduction in food intake. Studies in the author’s laboratory have used a transplantable Leydig cell tumor in Fischer rats. Food intake decreases by 20–40% and energy expenditure is greater than that of pair-fed controls. One mechanism that may be responsible for this relates to the postprandial metabolism of carbohydrate, since after a test meal there appears to be a greater rate of hepatic glycogen synthesis via the indirect pathway in tumor-bearing rats than in controls. The indirect pathway involves gluconeogenic enzymes, and studies using a variety of different tracers and enzyme inhibitors suggest that amino acids are important precursors. An increased rate of hepatic glycogen synthesis also appears to be maintained for a longer time after the meal in tumor-bearing rats, and this may act to delay the onset of the next meal, thereby explaining the decreased meal frequency that has been observed.