Sex-specific regulation of IL-10 production in human adipose tissue in obesity

Background Obesity-associated metabolic complications display sexual dimorphism and can be impacted by cytokines. We previously showed that interleukin-10 (IL-10) was upregulated in white adipose tissue (WAT) of obese women with type 2 diabetes (T2D). Whether this pertains to men is unknown. The aim of this study was to compare the impact of obesity and T2D on WAT IL-10 levels in men versus women. Methods Plasma and subcutaneous WAT biopsies were obtained from 108 metabolically well-characterized individuals. WAT IL10 expression/secretion and WAT-resident IL-10-secreting macrophage number were measured. Circulating sex hormone levels were correlated to WAT IL10 expression in 22 individuals and sex hormone effects on macrophage IL10 expression were investigated in vitro. Results Obese women with T2D showed increased IL10 expression/secretion and IL-10-secreting WAT macrophage number compared to other female groups. This difference was absent in men. Non-obese women and men with T2D showed similar IL-10 levels compared to healthy controls, indicating that T2D alone does not regulate IL-10. Although WAT IL10 expression correlated with serum estrone (E1) concentrations, recombinant E1 did not affect macrophage IL10 expression in vitro. Conclusion WAT IL-10 levels are higher in women with obesity and T2D, but not in men and this effect is primarily attributed to obesity per se. This is less likely to be driven by circulating sex hormones. We propose that the WAT IL-10 might exert protective effects in obesity-associated chronic inflammation in women which could be one of the contributing factors for the decreased morbidity observed in women during obesity than men.

[1]  P. Stadler,et al.  Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance , 2021, Gut.

[2]  I. Pantsulaia,et al.  ASSOCIATION OF IL-10 AND RESISTIN IN APPARENTLY HEALTHY ELDERLY POPULATION. , 2021, Georgian medical news.

[3]  F. Beguinot,et al.  Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes , 2020, Frontiers in Physiology.

[4]  K. Main,et al.  Sex-specific Estrogen Levels and Reference Intervals from Infancy to Late Adulthood Determined by LC-MS/MS , 2019, The Journal of clinical endocrinology and metabolism.

[5]  P. Arner,et al.  Human-specific function of IL-10 in adipose tissue linked to insulin resistance. , 2019, The Journal of clinical endocrinology and metabolism.

[6]  B. Stranger,et al.  ImmGen report: sexual dimorphism in the immune system transcriptome , 2019, Nature Communications.

[7]  K. Petersen,et al.  Anti‐inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid‐induced insulin resistance , 2019, The Journal of physiology.

[8]  P. Arner,et al.  Prospective analyses of white adipose tissue gene expression in relation to long-term body weight changes , 2019, International Journal of Obesity.

[9]  J. Smyth,et al.  Distinct inflammatory response patterns are evident among men and women with higher depressive symptoms , 2018, Physiology & Behavior.

[10]  N. Lefèvre,et al.  Differential Susceptibility to Infectious Respiratory Diseases between Males and Females Linked to Sex-Specific Innate Immune Inflammatory Response , 2017, Front. Immunol..

[11]  U. Turpeinen,et al.  Estrogen Metabolism in Abdominal Subcutaneous and Visceral Adipose Tissue in Postmenopausal Women , 2017, The Journal of clinical endocrinology and metabolism.

[12]  S. Huber,et al.  Age-Associated Changes in Estrogen Receptor Ratios Correlate with Increased Female Susceptibility to Coxsackievirus B3-Induced Myocarditis , 2017, Front. Immunol..

[13]  M. Altfeld,et al.  Human Immunodeficiency Virus 1 and Type I Interferons—Where Sex Makes a Difference , 2017, Front. Immunol..

[14]  K. Clément,et al.  Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue , 2017, Scientific Reports.

[15]  Sun-Hee Kim,et al.  Natural killer cell subsets and receptor expression in peripheral blood mononuclear cells of a healthy Korean population: Reference range, influence of age and sex, and correlation between NK cell receptors and cytotoxicity. , 2017, Human immunology.

[16]  P. Franks,et al.  Higher Prevalence of Type 2 Diabetes in Men Than in Women Is Associated With Differences in Visceral Fat Mass. , 2016, The Journal of clinical endocrinology and metabolism.

[17]  G. Hajishengallis,et al.  Sex dimorphism in periodontitis in animal models. , 2016, Journal of periodontal research.

[18]  P. Arner,et al.  Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes , 2016, Diabetologia.

[19]  S. Elsenbruch,et al.  Men and women differ in inflammatory and neuroendocrine responses to endotoxin but not in the severity of sickness symptoms , 2016, Brain, Behavior, and Immunity.

[20]  P. Arner,et al.  MAFB as a novel regulator of human adipose tissue inflammation , 2015, Diabetologia.

[21]  Mark M. Davis,et al.  Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination , 2013, Proceedings of the National Academy of Sciences.

[22]  C. Bai,et al.  Association between interleukin 1β and interleukin 10 concentrations: a cross-sectional study in young adolescents in Taiwan , 2013, BMC Pediatrics.

[23]  K. Hirokawa,et al.  Slower immune system aging in women versus men in the Japanese population , 2013, Immunity & Ageing.

[24]  H. Yoshimatsu,et al.  Obesity-related chronic kidney disease is associated with spleen-derived IL-10. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[25]  C. Apovian,et al.  B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile , 2013, Proceedings of the National Academy of Sciences.

[26]  A. Hevener,et al.  The role of estrogens in control of energy balance and glucose homeostasis. , 2013, Endocrine reviews.

[27]  H. Yoshimatsu,et al.  Spleen-Derived Interleukin-10 Downregulates the Severity of High-Fat Diet-Induced Non-Alcoholic Fatty Pancreas Disease , 2012, PloS one.

[28]  P. Carlsson,et al.  Female Mice are Protected against High-Fat Diet Induced Metabolic Syndrome and Increase the Regulatory T Cell Population in Adipose Tissue , 2012, PloS one.

[29]  J. Gugenheim,et al.  Identification of Adipose Tissue Dendritic Cells Correlated With Obesity-Associated Insulin-Resistance and Inducing Th17 Responses in Mice and Patients , 2012, Diabetes.

[30]  Piotr J. Balwierz,et al.  Adipose Tissue MicroRNAs as Regulators of CCL2 Production in Human Obesity , 2012, Diabetes.

[31]  H. Yoshimatsu,et al.  A novel anti‐inflammatory role for spleen‐derived interleukin‐10 in obesity‐induced hypothalamic inflammation , 2012, Journal of neurochemistry.

[32]  G. Bray,et al.  The Relationship of Waist Circumference and BMI to Visceral, Subcutaneous, and Total Body Fat: Sex and Race Differences , 2011, Obesity.

[33]  G. Smyth,et al.  Pro-Inflammatory CD11c+CD206+ Adipose Tissue Macrophages Are Associated With Insulin Resistance in Human Obesity , 2010, Diabetes.

[34]  T. Kadowaki,et al.  CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity , 2009, Nature Medicine.

[35]  C. Bouchard,et al.  Sex differences in inflammatory markers: what is the contribution of visceral adiposity? , 2009, The American journal of clinical nutrition.

[36]  J. Olefsky,et al.  Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. , 2008, Cell Metabolism.

[37]  K. Bost,et al.  Sexual dimorphism in expression of receptors for bacterial lipopolysaccharides in murine macrophages: a possible mechanism for gender-based differences in endotoxic shock susceptibility. , 2006, Journal of reproductive immunology.

[38]  M. Górska,et al.  Plasma interleukin-10 concentration is positively related to insulin sensitivity in young healthy individuals. , 2005, Diabetes care.

[39]  J. Tuomilehto,et al.  Sex differences in cardiovascular and total mortality among diabetic and non-diabetic individuals with or without history of myocardial infarction , 2005, Diabetologia.

[40]  V. Giusti,et al.  Adipose tissue is a regulated source of interleukin-10. , 2005, Cytokine.

[41]  V. Krenn,et al.  Sexual dimorphism in the osteoarthritis of STR/ort mice may be linked to articular cytokines , 2003, Annals of the rheumatic diseases.

[42]  E. Simpson.  Sources of estrogen and their importance , 2003, The Journal of Steroid Biochemistry and Molecular Biology.

[43]  R. A. Cassidy.  INFLUENCE OF STEROIDS ON OXIDANT GENERATION IN ACTIVATED HUMAN GRANULOCYTES AND MONONUCLEAR LEUKOCYTES , 2003, Shock.

[44]  R. Marfella,et al.  Association of low interleukin-10 levels with the metabolic syndrome in obese women. , 2003, The Journal of clinical endocrinology and metabolism.

[45]  D. Radzioch,et al.  Influence of gender and interleukin‐10 deficiency on the inflammatory response during lung infection with Pseudomonas aeruginosa in mice , 2002, Immunology.

[46]  C. Bouchard,et al.  The effect of sex, age and race on estimating percentage body fat from body mass index: The Heritage Family Study , 2002, International Journal of Obesity.

[47]  A. D. de Craen,et al.  Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes : the Leiden 85-Plus Study. , 2002, Diabetes.

[48]  S. Bulun,et al.  Estrogen production and action. , 2001, Journal of the American Academy of Dermatology.

[49]  E. Bruckert,et al.  Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. , 2000, The Journal of clinical endocrinology and metabolism.

[50]  D. Klinman,et al.  Sex hormone levels correlate with the activity of cytokine‐secreting cells in vivo , 2000, Immunology.

[51]  J. Correale,et al.  Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. , 1998, Journal of immunology.

[52]  J. Kato,et al.  Structure of aromatase mRNA in the rat brain , 1997, The Journal of Steroid Biochemistry and Molecular Biology.

[53]  B. Spiegelman,et al.  Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. , 1995, The Journal of clinical investigation.

[54]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[55]  S. Segal,et al.  Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse. , 1984, Journal of immunology.

[56]  H. Kley,et al.  Enhanced conversion of androstenedione to estrogens in obese males. , 1980, The Journal of clinical endocrinology and metabolism.

[57]  S. Tonstad,et al.  Determinants of inflammatory markers in a bi-ethnic population. , 2011, Ethnicity & disease.

[58]  I. Marriott,et al.  Sexual dimorphism in innate immune responses to infectious organisms , 2006, Immunologic research.

[59]  H. Hauner,et al.  Primary culture and differentiation of human adipocyte precursor cells. , 2005, Methods in molecular medicine.

[60]  J. Gussekloo,et al.  The Leiden 85-plus Study , 2000 .

[61]  H. Aoyama,et al.  Effects of sex hormones on chemotaxis of human peripheral polymorphonuclear leukocytes and monocytes. , 1992, Journal of periodontology.