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Critical Proteins and Their Change in Organism
Posted on: October 25, 2004

The Relationship between Body Composition and Metabolism

There is a large body of empiric evidence suggesting that changes in body composition reflect changes in metabolism of energy and protein within the body. For example, as lean mass is accrued during growth and adolescence, nitrogen balance is positive and protein metabolism favors synthesis. In obese subjects, there is a commensurate increase in fat mass and in fat oxidation. During starvation and under conditions of physiologic stress, loss of weight and negative elemental balances occur together. Thus, an underlying tenet of all research into the mechanisms of body composition change is that body composition is in equilibrium with metabolic state. However, whereas metabolism changes on a minute-to-minute basis, change in body composition is slower to be seen and slower to reverse. Thus, it may be said that body composition reflects the ''area under the curve'' of the organism's metabolic state – a catabolic organism will have a reduced lean mass and/or fat mass, whereas an obese organism will have an increased fat mass and (usually) lean mass. The slower time scale over which changes in body composition occur offers an opportunity to assess the nutritional and metabolic status of the organism over days, weeks or even years, depending on the pathophysiologic situation, rather than making the kind of kinetic minute-by-minute measurements required of metabolic assessment.

Hormonal Determinants of Quotidian Metabolism

On a day-to-day basis, energy and protein metabolism are controlled by insulin and glucagon. These two key housekeeping hormones operate against the background of a hormonal environment that is set by input from epinephrine, norepinephrine, thyroid hormones, corticosteroids, gonadal steroids, growth hormone and prolactin (Fig. 1). 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.

Fig. 1. Hormonal determinants of metabolism on three levels: daily, life cycle-related and stress-related.
IL = interleukin, TNF = tumor necrosis factor.

The Injury Response and the Role of the Immune System

When the organism is stressed by an injury, infection or illness, the daily swing of insulin- and glucagon-mediated metabolic shifts between fed and fasted states is disturbed. The organ system charged with recognizing and responding to an injury is the immune system, which has the capacity to radically change body protein and energy metabolism, and thus body composition. 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. 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 indifference terleukin-6 (IL-6). These three cytokines – IL-1, TNF and IL6 – are 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. 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. These metabolic alterations lead to profound changes in body composition. In experimental infection in rodents, albumin gene transcription decreases within 4 h of injury. 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.

Role of Cytokines in Cachexia: Examples

Scientists have shown that patients with rheumatoid arthritis, the most common adult autoimmune condition, are hypermetabolic, hypercatabolic and cachectic. In this population, production of IL-1 and TNF explains 20% of the variability in resting energy metabolism, whereas no such association exists in healthy age-, sex-, race-, and weight-matched controls. There is also a strong correlation (r = 0.47, P < 0.01) between whole-body protein breakdown and TNF production by peripheral blood mononuclear cells. In addition, we found that both glucagon and growth hormone were strongly related to protein metabolism in this population, with growth hormone inversely correlated with protein breakdown and glucagon inversely correlated with protein synthesis. It is noteworthy that we could not find an association between cytokine production and body composition measurements either in rheumatoid arthritis or in normal aging. This may be well due to the different timetables involved; cytokine production varies from minute to minute, whereas body composition changes over years in chronic inflammation and aging. To address this issue directly, we turned to an animal model of chronic inflammation, using adjuvant arthritis in the Lewis rat. 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. Scientists investigated cytokine production in aging in subjects who participated in the Framingham Heart Study. There was no indifference in the production of IL-1 or TNF by peripheral blood mononuclear cells from elderly subjects (mean age 78 years) 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. These data suggest that aging is associated with a dysregulation of cytokine production that could lead to a predisposition to sarcopenia.

Studies performed over the past decade suggest that body composition is an important biomarker of physiologic status, because body composition is in equilibrium with energy and protein metabolic state. In addition to the daily hormonal regulation of metabolism in health, an additional level of regulation occurs at the hormonal level that responds to the life cycle of the organism. During times of injury, the immune system – acting through the inflammatory cytokines IL-1, TNF and IL-6 – becomes a key regulator of metabolism and thus of body composition. These cytokines, which affect metabolism indirectly by altering secretion of endocrine hormones and directly by affecting target organs, act as a third level of regulation of body composition. It remains unclear whether there is a regulatory role for the cytokines in the absence of an acute or chronic inflammatory stimulus. However, the ability of these cytokines to cause catabolism suggests that they could play a role in the development of age-related sarcopenia in ways that are not currently understood.

Source: R. Roubenoff, Inflammatory and Hormonal Mediators of Cachexia. American Society for Nutritional Sciences. 1014S-1016S. 1997
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