Lymphocyte roles in metabolic dysfunction: of men and mice
2015; Elsevier BV; Volume: 26; Issue: 2 Linguagem: Inglês
10.1016/j.tem.2014.12.001
ISSN1879-3061
AutoresBlanche C. Ip, Andrew E. Hogan, Barbara S. Nikolajczyk,
Tópico(s)IL-33, ST2, and ILC Pathways
Resumo•Lymphocytes have complex regulatory roles in obesity-associated insulin resistance and type 2 diabetes pathogenesis.•Obesity differentially impacts the frequencies and behaviors of lymphocyte subsets.•Lymphocytes interact with other immune cells and with adipocytes to regulate adipose tissue inflammation.•Differences between type 2 diabetes in animals and humans indicate the value of a bedside-to-bench approach to maximize clinical impact of future studies. Type 2 diabetes (T2D) is a metabolic disease associated with obesity-related insulin resistance (IR) and chronic inflammation. Animal studies indicate that IR can be caused and/or exacerbated by systemic and/or tissue-specific alterations in lymphocyte differentiation and function. Human studies also indicate that obesity-associated inflammation promotes IR. Nevertheless, clinical trials with anti-inflammatory therapies have yielded modest impacts on established T2D. Unlike mouse models, where obesity is predominantly associated with IR, 20–25% of obese humans are metabolically healthy with high insulin sensitivity. The uncoupling of obesity from IR in humans but not in animal models advocates for a more comprehensive understanding of mediators and mechanisms of human obesity-promoted IR, and better integration of knowledge from human studies into animal experiments to efficiently pursue T2D prevention and treatment. Type 2 diabetes (T2D) is a metabolic disease associated with obesity-related insulin resistance (IR) and chronic inflammation. Animal studies indicate that IR can be caused and/or exacerbated by systemic and/or tissue-specific alterations in lymphocyte differentiation and function. Human studies also indicate that obesity-associated inflammation promotes IR. Nevertheless, clinical trials with anti-inflammatory therapies have yielded modest impacts on established T2D. Unlike mouse models, where obesity is predominantly associated with IR, 20–25% of obese humans are metabolically healthy with high insulin sensitivity. The uncoupling of obesity from IR in humans but not in animal models advocates for a more comprehensive understanding of mediators and mechanisms of human obesity-promoted IR, and better integration of knowledge from human studies into animal experiments to efficiently pursue T2D prevention and treatment. T2D is a chronic disease characterized by metabolic dysfunction, including hyperglycemia, pancreatic beta cell insufficiency, and IR (see Glossary). IR can be driven by calorie surplus that leads to obesity, although a significant subgroup of obese individuals, the metabolic healthy obese (MHO), have healthy metabolic profiles [1Samocha-Bonet D. et al.Metabolically healthy and unhealthy obese: the 2013 Stock Conference report.Obes. Rev. 2014; 15: 697-708Crossref PubMed Scopus (1) Google Scholar, 2Denis G.V. Obin M.S. 'Metabolically healthy obesity': origins and implications.Mol. Aspects Med. 2013; 34: 59-70Crossref PubMed Scopus (19) Google Scholar]. Metabolic unhealthy obese (MUHO) have metabolic profiles that mirror profiles of individuals with T2D. Up to 30% of MHO can convert to MUHO over a 5–10-y timeframe [1Samocha-Bonet D. et al.Metabolically healthy and unhealthy obese: the 2013 Stock Conference report.Obes. Rev. 2014; 15: 697-708Crossref PubMed Scopus (1) Google Scholar, 3Lee C.T. et al.White blood cell subtypes, insulin resistance and beta-cell dysfunction in high-risk individuals: the PROMISE cohort.Clin. Endocrinol. (Oxf.). 2014; 81: 536-541Crossref PubMed Google Scholar, 4Achilike I. et al.Predicting the development of the metabolically healthy obese phenotype.Int. J. Obes. (Lond.). 2014; (Published online July 2, 2014)https://doi.org/10.1038/ijo.2014.113Crossref PubMed Google Scholar], fueling the debate over the existence of a stable MHO subset. Identification of the mechanisms that promote (or prevent) the transition from MHO to MUHO to delay T2D will be crucial to counter the public health burden of metabolic disease. Adipose tissue (AT) adipocytes undergo hyperplasia and hypertrophy to accommodate the increased demand of triglyceride storage in response to overnutrition [5Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (2535) Google Scholar]. Adipose-resident immune cells have critical roles during AT remodeling, in part through cytokine secretion that facilitates the vascular and extracellular matrix remodeling required for healthy AT expansion [6Wernstedt Asterholm I. et al.Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling.Cell Metab. 2014; 20: 103-118Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. If AT inflammation is suppressed in this context, AT dysfunction and systemic metabolic disturbances ensue [6Wernstedt Asterholm I. et al.Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling.Cell Metab. 2014; 20: 103-118Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Chronic AT expansion during the development of obesity induces excessive immune cell recruitment and accumulation [7Oh D.Y. et al.Increased macrophage migration into adipose tissue in obese mice.Diabetes. 2012; 61: 346-354Crossref PubMed Scopus (68) Google Scholar], and modulates 'innate' (nonlymphocyte) and 'adaptive' (lymphocyte) immune cells (Table 1) [8Dalmas E. et al.T cell-derived IL-22 amplifies IL-1beta-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes.Diabetes. 2014; 63: 1966-1977Crossref PubMed Scopus (8) Google Scholar], with shifts in AT immune cells somewhat mirrored in blood (Table 2) and liver [9Gadd V.L. et al.The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease.Hepatology. 2014; 59: 1393-1405Crossref PubMed Scopus (5) Google Scholar]. Chronic AT expansion also induces adipocyte transformation, including altered intracellular gene and protein expression, adipokine secretion, and apoptotic signals [10Nakamura K. et al.Adipokines: a link between obesity and cardiovascular disease.J. Cardiol. 2014; 63: 250-259Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 11Procaccini C. et al.Role of adipokines signaling in the modulation of T cells function.Front. Immunol. 2013; 4: 332Crossref PubMed Google Scholar, 12Ohashi K. et al.Role of anti-inflammatory adipokines in obesity-related diseases.Trends Endocrinol. 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Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google ScholarNANo difference 122Esser N. et al.Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue.Diabetologia. 2013; 56: 2487-2497Crossref PubMed Scopus (18) Google ScholarIncreased 29Yang H. et al.Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance.J. Immunol. 2010; 185: 1836-1845Crossref PubMed Scopus (98) Google ScholarEffector and/or memory CD8+ (%)Subcutaneous: increased 29Yang H. et al.Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance.J. 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Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google ScholarNo difference 15Fabbrini E. et al.Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals.Gastroenterology. 2013; 145 (e363): 366-374Abstract Full Text Full Text PDF PubMed Scopus (18) Google ScholarNo difference 15Fabbrini E. et al.Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals.Gastroenterology. 2013; 145 (e363): 366-374Abstract Full Text Full Text PDF PubMed Scopus (18) Google ScholarNATh1 (no.)Subcutaneous and visceral: increased 22Winer S. et al.Normalization of obesity-associated insulin resistance through immunotherapy.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google ScholarNANANATh2 (%)Visceral: decreased 22Winer S. et al.Normalization of obesity-associated insulin resistance through immunotherapy.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google ScholarNo difference 15Fabbrini E. et al.Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals.Gastroenterology. 2013; 145 (e363): 366-374Abstract Full Text Full Text PDF PubMed Scopus (18) Google ScholarNo difference 15Fabbrini E. et al.Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals.Gastroenterology. 2013; 145 (e363): 366-374Abstract Full Text Full Text PDF PubMed Scopus (18) Google ScholarNATh17 (%)Subcutaneous: no difference 22Winer S. et al.Normalization of obesity-associated insulin resistance through immunotherapy.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google Scholar or increased 51Zúñiga L.A. et al.IL-17 regulates adipogenesis, glucose homeostasis, and obesity.J. 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Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google Scholar, 51Zúñiga L.A. et al.IL-17 regulates adipogenesis, glucose homeostasis, and obesity.J. Immunol. 2010; 185: 6947-6959Crossref PubMed Scopus (65) Google Scholar; visceral: no difference 22Winer S. et al.Normalization of obesity-associated insulin resistance through immunotherapy.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google ScholarNANANATreg (%)Visceral: decreased 22Winer S. et al.Normalization of obesity-associated insulin resistance through immunotherapy.Nat. Med. 2009; 15: 921-929Crossref PubMed Scopus (424) Google Scholar, 67Feuerer M. et al.Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.Nat. Med. 2009; 15: 930-939Crossref PubMed Scopus (496) Google ScholarDecreased 67Feuerer M. et al.Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.Nat. 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Chem. 2012; 287: 13561-13571Crossref PubMed Scopus (53) Google ScholarNADecreased: iNKT (BMI >40, T2D status unknown) 86Lynch L. et al.Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production.Immunity. 2012; 37: 574-587Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 106Lynch L.A. et al.Are natural killer cells protecting the metabolically healthy obese patient?.Obesity. 2009; 17: 601-605Crossref PubMed Scopus (52) Google ScholarB cell (no.)Visceral: increased 23Duffaut C. et al.Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity.Biochem. Biophys. Res. Commun. 2009; 384: 482-485Crossref PubMed Scopus (101) Google Scholar, 35Winer D.A. et al.B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.Nat. Med. 2011; 17: 610-617Crossref PubMed Scopus (187) Google ScholarNANANAILC2 (%)Visceral: decreased 101Nussbaum J.C. et al.Type 2 innate lymphoid cells control eosinophil homeostasis.Nature. 2013; 502: 245-248Crossref PubMed Scopus (50) Google ScholarNANANA Open table in a new tab Table 2Lymphocyte subsets in systemic circulationaLymphocyte subsets in mouse systemic circulation have not been elucidated.SignaturesHumanT2D versus non-T2DMUHO versus MHOObese (non-T2D) versus leanCD8+ (%)NADecreased 106Lynch L.A. et al.Are natural killer cells protecting the metabolically healthy obese patient?.Obesity. 2009; 17: 601-605Crossref PubMed Scopus (52) Google Scholar; no difference (women) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarDecreased 106Lynch L.A. et al.Are natural killer cells protecting the metabolically healthy obese patient?.Obesity. 2009; 17: 601-605Crossref PubMed Scopus (52) Google Scholar, 123O'Rourke R.W. et al.Alterations in T-cell subset frequency in peripheral blood in obesity.Obes. Surg. 2005; 15: 1463-1468Crossref PubMed Scopus (43) Google Scholar; no difference (women) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarCD8+ (no.)NANo difference (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarNo difference (BMI >40 versus 40 versus 40 versus 40 versus 40 versus 40 versus 40, T2D status unknown) 86Lynch L. et al.Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production.Immunity. 2012; 37: 574-587Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarB cell (%)NANo difference (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarNAB cell (no.)NANo difference (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarNo difference (BMI >40 versus <25) 124van der Weerd K. et al.Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype.Diabetes. 2012; 61: 401-408Crossref PubMed Scopus (23) Google Scholar; no difference (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarCD19+ CD38+ (%)NANo difference (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarIncreased (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarCD19+ CD27+ (%)NANo difference (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google ScholarNo difference (females) 14van Beek L. et al.Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance.Metabolism. 2014; 63: 492-501Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholara Lymphocyte subsets in mouse systemic circulation have not been elucidated. Open table in a new tab Chronic 'low-grade' inflammation observed in IR and T2D has a critical role in T2D pathogenesis, partially through the ability of proinflammatory cytokines to impai
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