The study of body composition has long concerned itself with improvements in the measurements of body compartments. Over the past several years, five categories of body compartments have been developed by the group at St. Luke's-Roosevelt Hospital (New York City) indicating our progress from the whole-body to the atomic level of integration of body composition measurements (Wang et al. 1992). However, as our ability to define body composition has evolved, it has become clear that we must push the boundaries of body composition science in two other directions: first, in a more basic direction to understand the metabolic, hormonal and immune mediators of change in body composition through the life cycle and in illness, and second, in a more applied direction to understand how changes in body composition translate into changes in physiology, functional status, and quality and duration of life. This article will address a small subset of this charge: the potential hormonal and inflammatory mediators of change in body composition, using cachexia as a paradigm.

THE RELATIONSHIP BETWEEN BODY COMPOSITION AND METABOLISM

HORMONAL DETERMINANTS OF QUOTIDIAN METABOLISM

In a healthy state, vertebrates alternate between the fed and fasted states, which are internally recognizable by the presence of high and low insulin levels, respectively. Insulin and glucagon respond to a meal within minutes, and their levels fall as the meal is digested. This system allows a quick and efficient response to daily metabolic perturbations. Additional inputs from estrogens, androgens, thyroid hormones, growth hormone and prolactin alter metabolism in relation to the organism's life cycle. Thus, the gonadal steroids and growth hormone increase at puberty to create a more anabolic animal, and they decline in senescence as sarcopenia develops. The catecholamines and thyroid hormones further modulate metabolism in response to acute insults, illness, etc.

THE INJURY RESPONSE AND THE ROLE OF THE IMMUNE SYSTEM

The antigen-presenting cell (APC) of the immune system is typically a macrophage, tissue monocyte or skin dendritic cell. The APC contacts an antigen, phagocytoses it, processes an antigenic determinant, and brings it to its surface in an HLA-restricted manner in order to trigger an immune response (Roitt et al. 1989). This immune response requires both the presence of a specific epitope from the antigen and the elaboration of one or more nonspecific signals, chiefly via secretion of the cytokine interleukin-1 (IL-1). Interleukin-1 secretion triggers activation of T cells and other portions of the immune response.

Subsequent APC-initiated signals include the elaboration of tumor necrosis factor (TNF) and, later, production of interleukin-6 (IL-6). These three cytokinesIL-1, TNF and IL-6are currently thought to play the most important roles in the development of the acute-phase metabolic response, which parallels the acute-phase immune response. Because there are receptors for these cytokines on every cell in the body except red blood cells, these cytokines have profound effects on the hormones that govern metabolism as well as acting directly on the metabolic target organs such as muscle, liver, gut and brain (Pomposelli et al. 1988). The result is an increase in resting energy expenditure, a net export of amino acids from muscle to liver, an increase in gluconeogenesis, and a marked shift in liver protein synthesis away from albumin and toward production of acute-phase proteins such as fibrinogen and C-reactive protein (Kushner 1993).

These metabolic alterations lead to profound changes in body composition. In experimental infection in rodents, albumin gene transcription decreases within 4 h of injury (Princen et al. 1983). In human volunteers given a controlled infection, nitrogen balance turns negative in 24 h. Changes in body composition generally become measurable within a few days to a week, depending on the sensitivity of the body composition technique being used (Hill 1992).

ROLE OF CYTOKINES IN CACHEXIA: EXAMPLES

To address this issue directly, we turned to an animal model of chronic inflammation, using adjuvant arthritis in the Lewis rat (Roubenoff et al. 1997). In this situation, we have shown that inflammation is associated with wasting and anorexia, both of which begin before the onset of clinical arthritis. In this model, TNF production correlates well with weight loss (r = 0.68, P < 0.007).

Additional evidence for a connection between cytokines and body composition comes from studies performed by Freeman and Roubenoff (1994) in a canine model of congestive heart failure. As in humans with congestive heart failure, dogs with congestive heart failure have elevated production of TNF and IL-1. Our data indicated that a decline in IL-1 is a significant predictor of survival in congestive heart failure, suggesting that anti-cytokine interventions may be important in modulating the course of this increasingly prevalent and deadly disease.

Finally, the catabolic capacity of the inflammatory cytokines suggests that they could play a role in sarcopenia as well. We investigated cytokine production in aging in subjects who participated in the Framingham Heart Study. There was no difference in the production of IL-1 or TNF by peripheral blood mononuclear cells from elderly subjects (mean age 78 y) compared with young healthy controls. However, there was a marked increase in production of both IL-6 and the anti-inflammatory cytokine interleukin-1 receptor antagonist (Freeman, L. M., unpublished data). These data suggest that aging is associated with a dysregulation of cytokine production that could lead to a predisposition to sarcopenia.

CONCLUSION