Molecular Basis of Inflammation: Relationships Between Catabolic Cytokines, Hormones, Energy Balance, and MuscleFrom Immunology R&D, Biogen Idec, Cambridge, Massachusetts, and Tufts University, Boston, Massachusetts. Address correspondence to: Ronenn Roubenoff, MD, MHS, Immunology R&D, Biogen Idec, 12 Cambridge Center, B6a-6, Cambridge, MA 02142; e-mail: Ronenn.Roubenoff{at}biogenidec.com.
Inflammation alters energy metabolism, macro- and micronutrient balances, and body composition. This review briefly describes the current understanding of how this happens, focusing on the effect of immune system activation on energy balance. Conversely, malnutrition also has a large impact on immune function, with both undernutrition (causing immune suppression) and overnutrition (causing inflammation) now well described. Improved understanding of the interplay of the immune system and metabolism can lead to new treatments for both cachexia and obesity.
Key Words: immune system • inflammation • metabolism • energy deficit • protein • malnutrition • acute illness The goal of this presentation is to briefly discuss our current understanding of answers to these 4 questions:
The reader should recognize that this is a rapidly changing field with a great deal of active investigation, so this review is neither comprehensive nor guaranteed against being outdated. 1. How do humans regulate energy balance?
Our understanding of the neuroendocrine pathways that control appetite
(energy intake) and physical activity (the major determinant, along with
resting energy expenditure (REE), of energy output) has exploded in recent
years.1 Humans are
subject to the laws of thermodynamics just like everything else, so if energy
intake exceeds energy expenditure, weight must increase, whereas if the
opposite is true, weight must decrease. This is expressed by the energy
balance equation
Control of appetite and physical activity occurs in the arcuate nucleus,
lateral hypothalamus, and paraventricular nucleus of the brain
(Figure 1). A complex web of
positive and negative signals with activating and inhibitory inputs determines
energy balance. At least 3 key neurotransmitters in the brain stimulate
appetite (or neuropeptide Y [NPY]; galanin; and agouti-related protein
[AGRP]), whereas at least 4 others suppress it (
2. Is muscle nutrient balance regulated differently from whole-body energy balance? Muscle, as the major protein store in the body, is called on to release amino acids for use in creating new proteins when dietary amino acids are not available. Thus, protein degradation in the muscle and energy balance at the whole-body level are closely related; it is estimated that about 20% of REE is due to protein turnover.3 Control of muscle protein breakdown has its own set of inhibitory and activating signals, which come together at a kinase called S6K1.4 The PI3K-Akt-Rheb-mTOR-S6K1 signaling network receives input from various stimuli such as nutrients, growth factors, and exercise, which can modulate it at various levels. In general, activation of PI3K indirectly regulates Akt, whose activity prevents tuberous-sclerosis complex-2 (TSC2)–mediated inhibition of Rheb. When bound to guanosine triphosphate (GTP), Rheb increases mammalian target of rapamycin (mTOR) activity toward S6K1 and other translational-control factors (not shown). S6K1 controls muscle size, as its absence results in a marked reduction in muscle mass. Genetic deletion of S6K1 also leads to increased adenosine monophosphate (AMP) levels, causing an "energy stress" state that is sensed by AMP-activated protein kinase (AMPK), which induces an increase in mitochondrial mass and oxidative metabolism. An increase in AMPK can also lead to the activation of TSC2, thereby inhibiting signals that can affect the regulation of muscle size.4 It is clear that inadequate protein intake over weeks is sufficient to cause muscle wasting.5 Conversely, resistance exercise is more important than nutritional supplementation in preventing muscle wasting in the presence of adequate protein intake, even if energy intake is subpar (N. Brooks, C. Castaneda, R. Roubenoff, et al, unpublished). Muscle, like bone, is very plastic and responds to load bearing with growth. Both organs are also very sensitive to inflammation, as discussed below. 3. Is there a role for the immune system in this regulation? The ability of the immune system to cause energy and protein metabolic disruption is readily demonstrated in a variety of diseases. One of the most studied has been rheumatoid cachexia (RC), a consequence of rheumatoid arthritis (RA), the most common autoimmune disease in adults. Rheumatoid cachexia is a state of elevated REE, reduced EEPA, and profound loss of muscle mass and strength.6 Rheumatoid arthritis is a state of hypercytokinemia, with elevated production of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and many other cytokines.7 TNF especially has been implicated as the cause of RC, with additional contributions from IL-1β. Treatment of RA with TNF inhibitors has been shown to halt RC, although it seems likely that only an additional anabolic stimulus, such as resistance exercise, can actually reverse it.8 4. What are the implications of this for treatment? Nature has provided a simple and effective treatment for unbalanced energy and protein metabolism due to inflammation: exercise. For example, 12 weeks of strength training can reverse about half the decline in strength and muscle mass that occurs over 12 years in healthy elderly adults.9 However, pharmacological attempts to mimic the benefit of exercise have not been successful so far. Androgens, growth hormone, and appetite stimulants have modest anabolic effects and potentially important toxicities. For obesity, serotonin receptor and cannabinoid receptor antagonists have modest efficacy at best. For now, exercise remains the cornerstone of any attempts to treat immune-mediated energy and protein dysmetabolism.
Financial disclosure: none declared. The 2008 Intersociety Research Workshop: Nutrition and Inflammation: Research Makes the Connection, was supported by grant number U13DK064190 from the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health.
Journal of Parenteral and Enteral Nutrition, Vol. 32, No. 6,
630-632 (2008)
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-MSH, or melanocyte
stimulating hormone; a family of peptides called orexins; neurotensin; and
cocaine- and amphetamine-related transcript [CART]). These, in turn, are
activated or suppressed by leptin, ghrelin, and insulin, signals that
originate in the adipose tissue, stomach, and pancreas, respectively. The
balance of these signals varies according to the person's physiological state,
but Schwartz et al
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