Review
When diet and exercise are not enough, think immunomodulation

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Abstract

The incidences of obesity and Type 2 Diabetes (T2D) are rapidly on the rise and now considered global health epidemics. Clinical data indicate a physiologically critical connection between the metabolic and immune systems, as obese individuals are uniquely susceptible to infectious and autoimmune diseases. We discuss the relevance of mouse models of obesity and the potential development of a ‘biomarker toolkit’ from human blood, along with the current knowledge regarding immune cell profiles in blood and adipose tissue of obese individuals with or without concomitant diseases such as T2D and Metabolic Syndrome. Understanding how the immune system initiates, perpetuates, and/or exacerbates obesity-associated diseases could lead to novel immune-based therapies for the abrogation of disease progression especially in pre-diabetic patients.

Section snippets

Introduction: the relationship between obesity and immunity

Excess adiposity is directly linked to Metabolic Syndrome and Type 2 Diabetes (T2D), two diseases associated with marked immune aberrancies. Not all obese individuals are metabolically compromised, however, with 3–43% percent classified as “Metabolically Healthy Obese” (MHO), depending on the criteria used (Velho et al., 2010). Obesity is linked to increased susceptibility to and/or progression of a variety of infectious diseases, including influenza (Davalos Moscol, 2010, Morgan et al., 2010),

Use of mouse models to understand human metabolic disease

Research into causes and treatments of obesity and T2D often utilizes animals, and recent work continues to exploit the strengths of mouse models. Such studies are absolutely required to test hypotheses in complex in vivo settings that cannot be recapitulated by purified cells or other ex vivo disease models. These models have many benefits, including the ability to understand whole animal responses to hyper-nutrition, a common underlying cause of metabolic disease. Work on numerous genetically

Can human blood provide novel biomarkers for T2D severity and clinical trial outcomes?

The most commonly used parameter to assess T2D severity or T2D drug efficacy is normalization of blood glucose/glycated hemoglobin levels, although more recent studies have also included inflammatory markers and the stress induced C reactive protein (Salomaa et al., 2010). New work is slowly eroding some of the justification for exclusive focus on tight glucose regulation (Duckworth et al., 2009, Holman et al., 2008, Patel et al., 2008, Turnbull et al., 2009), and many patients that maintain

T cells: defining the subsets

One predominant immune cell subset in human blood that is linked to metabolic changes in mouse studies is the T cell. T cells can be classified by phenotypic expression of surface antigens (CD4, CD8) or by functional profile (e.g. Th1, Th2, Th17, Treg). T cells of the Th1 and Th17 lineages contribute to viral and bacterial control and can also cause immunopathology. These ‘Type 1’ T cells secrete cytokines such as IFN-γ, TNF-α, and IL-17 and also can directly kill target cells via perforin

T cells: altered distribution of inflammatory and immunosuppressive subsets with high BMI

Alterations of T cell subset frequencies and functional profiles in obese individuals are still largely unknown. The response of peripheral blood T cells is significantly more Th17-dominant in individuals with T2D compared with ND subjects, implicating Th17 cells in T2D pathogenesis (Jagannathan-Bogdan et al., 2011). Th1 function is also elevated in T2D patients (Jagannathan-Bogdan et al., 2011). Analysis of tissue sections of human VAT revealed that a higher Tbet (Th1): to FOXP3 (Treg) ratio,

B cells promote inflammation in T2D

Work from our lab and others generally supports the conclusion that B cells promote disease pathogenesis in T2D. B cells from the blood of obese T2D patients constitutively secrete the pro-inflammatory cytokine/chemokine IL-8, and IL-8 production increases significantly in response to B cell stimulation (Jagannathan et al., 2010). Importantly, B cells from these patients fail to produce significant levels of anti-inflammatory IL-10 (Jagannathan et al., 2010). Lack of B cell IL-10 has

Natural Killer (NK) cells: functionally impaired in the unhealthy obese

NK cells are a subset of CD3 lymphocytes that comprise ∼10% of PBMC in humans (Moretta et al., 2002), and are integral to the control of viral infections (Biron et al., 1999, Kuijpers et al., 2008). NK cells also contribute to tumor surveillance (Smyth et al., 2002). This lymphocyte subset has both innate and adaptive immune functions, and responds to a loss of MHC antigens on target cells in a non-antigen specific manner. In addition, NK cells undergo ‘selective education’ and clonal

Natural Killer T (NKT) cells: do they control disease progression in obese individuals?

Natural Killer T (NKT) cells are a rare subset of T cells that secrete a variety of cytokines from different T cell subsets (Snyder-Cappione et al., 2010). NKT cells are instrumental in the control/pathogenesis of infectious and autoimmune diseases as well as cancer, where they are now being targeted in clinical trials (Motohashi and Nakayama, 2008). Administration of NKT-specific antigen alpha-galactosylceramide to mice after 13 weeks on HFD increased infiltration of macrophage into adipose

Antigen presenting cell subsets differentially influence obesity-associated diseases

The priming of the adaptive immune system requires stimulation via antigen presenting cells (APCs). APCs can alternatively differentiate based on cytokine-dependent mechanisms and secrete distinct patterns of effector molecules. For example, IFN-γ and TNF-α, prototypical Th1 cytokines, classically activate macrophages to a pro-inflammatory phenotype (reviewed in Mosser, 2003). IL-4 alternatively activates macrophages, dramatically increasing their ability to degrade phagocytosed proteins, a

Recruitment of immune cells to the adipose tissue

Understanding the mechanism by which immune cells infiltrate adipose tissue may enable the development of novel therapeutics to combat obesity-related inflammatory diseases. Higher levels of RANTES and CCR5 mRNA are found in human subcutaneous adipose tissue from individuals with metabolic syndrome compared with lean subjects (Wu et al., 2007). In human VAT, RANTES mRNA levels correlated with both CD3 and CD11b mRNA, markers of T cells and macrophages, respectively (Wu et al., 2007). Human

Conclusions/Model

Fig. 2 summarizes the current knowledge of the status of the cellular immune system in obesity. First, it is important to note that Fig. 2A and B are defined status of the adipose tissue in ‘lean’ and ‘obese’ states, respectively; however, the exact immune status of MHO individuals remain to be determined. The overall status of the ex vivo functional capacity of immune cells from the blood of obese individuals is currently unclear, with some reports of lower T cell proliferative capacity and

Acknowledgements

We would like to thank Marie McDonnell and Amedeo Cappione III for critical reviews of this manuscript. Susan Fried, Martin Obin, Gerald Denis, Madhumita Jagannathan-Bogdan and Anna Belkina provide ongoing thoughtful conversations on immunometabolism. This work was supported by National Institutes of Health Grant R21DK089270 and the Boston Nutrition Obesity Research Center.

Dr. Snyder-Cappione earned her Ph.D. from the Department of Microbiology and Immunology at the University of Rochester Medical Center, where she studied the regulation of effector functions of CD8+ T cells. During her post-doctoral work at UCSF, she investigated the role of iNKT cells in many diseases, including HIV and Mycobacterium tuberculosis. Her current research interests include determining the diagnostic and prognostic potential of ex vivo immune functional profiling in human

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  • Dr. Snyder-Cappione earned her Ph.D. from the Department of Microbiology and Immunology at the University of Rochester Medical Center, where she studied the regulation of effector functions of CD8+ T cells. During her post-doctoral work at UCSF, she investigated the role of iNKT cells in many diseases, including HIV and Mycobacterium tuberculosis. Her current research interests include determining the diagnostic and prognostic potential of ex vivo immune functional profiling in human inflammatory diseases.

    Dr. Nikolajczyk earned her Ph.D. in Anatomy and Cell Biology from the University of North Carolina at Chapel Hill, specializing in cell biology of reproduction. Her complementary post-doctoral training in molecular immunology at Brandeis University has served as the foundation for her unique approach to understanding the role the immune system plays in obesity and type 2 diabetes. Her recent work has focused on human immune cell analyses with the use of preclinical mouse models to highlight the importance of bedside-to-bench approaches for establishing new concepts in immunometabolism.

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