Trends in Immunology
ReviewThe immunomodulating role of exercise in metabolic disease
Section snippets
Inflammation at the nexus of metabolic disease
The World Health Organization has estimated that in excess of 1 billion people worldwide are overweight, with 300 million defined as clinically obese. Obesity is associated with the development of a cluster of chronic metabolic diseases such as insulin resistance, type 2 diabetes, atherosclerosis, nonalcoholic liver disease, hypertension, and some forms of cancer [1]. Physical inactivity is major contributor to the development of chronic metabolic diseases [2]. Furthermore, regular exercise
Obesity and adipose tissue-resident immune cells
A hallmark of obesity is a shift in the immune cell profile of the adipose tissue [8]. Thus, the proportion of resident M2 anti-inflammatory, alternatively activated macrophages [15], eosinophils [16], and CD4+ T lymphocytes [17] decreases and the proportions of M1 proinflammatory, classically activated macrophages [15], neutrophils [18], B lymphocytes [19] and CD8+ T lymphocytes [17] are increased. Mechanistically, this change in the adipose tissue immune cell profile initiates a state of
Exercise and lipid accumulation and inflammation in liver and skeletal muscle
Hepatic lipid accumulation is a central feature of several metabolic diseases. For example, excess hepatic lipid accumulation induces hepatic insulin resistance leading to elevated hepatic glucose production and hyperglycemia and plays a key role in the development of nonalcoholic fatty liver disease. Although excess hepatic lipid accumulation is likely to exert deleterious actions via multiple mechanisms, increased liver inflammation is a hallmark of hepatosteatosis and has been
Exercise ameliorates TLR-dependent inflammation
The TLRs are a family of transmembrane receptors that are central to innate immunity [44]. However, in addition to their central role in regulating responses to pathogens, the activation of specific TLRs, most notably TLR4, has been suggested to play a role in the development of obesity-induced insulin resistance, type 2 diabetes, and atherosclerosis 45, 46. Lipopolysaccharide (LPS), a component of the outer cell wall of Gram-negative bacteria, is the canonical ligand for TLR4. However, in
Exercise tempers inflammatory signals upstream and downstream of IL-1
Proinflammatory cytokines are elevated in numerous metabolic diseases [1]. Although mechanistic roles have been described for some of these, the cytokine that is perhaps best characterized in terms of its involvement in disease pathogenesis is IL-1β [72]. IL-1β is a master cytokine, controlling local and systemic inflammation [72]. IL-1β levels are increased in and have been shown to contribute to numerous metabolic diseases, including atherosclerosis, obesity-induced insulin resistance [73],
Concluding remarks and outlook
As discussed above, the adipose tissue immune cell profile changes dramatically in the transition from the lean to the obese state. Numerous immune cell types have been shown to contribute to adipose tissue inflammation and systemic insulin resistance in the obese state or, by contrast, contribute to the maintenance of insulin sensitivity in the lean, healthy state [8]. This raises several important questions for further research. First, does exercise prevent the accumulation of other immune
Acknowledgments
The authors thank all of their current and past staff and collaborators who have contributed to this body of work. They gratefully acknowledge the Australian Research Council and the National Health and Medical Research Council (NHMRC) for continued funding support. M.A.F. is a Senior Principal Research Fellow of the NHMRC.
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