Impact of obesity on IL-12 family gene expression in insulin responsive tissues.

Mounting evidence has established a role for chronic inflammation in the development of obesity-induced insulin resistance, as genetic ablation of pro-inflammatory cytokines and chemokines elevated in obesity improves insulin signaling in vitro and in vivo. Recent evidence further highlights interleukin (IL)-12 family cytokines as prospective inflammatory mediators linking obesity to insulin resistance. In this study, we present empirical evidence demonstrating that IL-12 family related genes are expressed and regulated in insulin-responsive tissues under conditions of obesity. First, we report that respective mRNAs for each of the known members of this cytokine family are expressed within detectable ranges in WAT, skeletal muscle, liver and heart. Second, we show that these cytokines and their cognate receptors are divergently regulated with genetic obesity in a tissue-specific manner. Third, we demonstrate that select IL-12 family cytokines are regulated in WAT in a manner that is dependent on the developmental stage of obesity as well as the inflammatory progression associated with obesity. Fourth, we report that respective mRNAs for IL-12 cytokines and receptors are also expressed and divergently regulated in cultured adipocytes under conditions of inflammatory stress. To our knowledge, this report is the first study to systemically evaluated mRNA expression of all IL-12 family cytokines and receptors in any tissue under conditions of obesity highlighting select family members as potential mediators linking excess nutrient intake to metabolic diseases such as insulin resistance, diabetes and heart disease.

[1]  B. Gustafson.  Adipose tissue, inflammation and atherosclerosis. , 2010, Journal of atherosclerosis and thrombosis.

[2]  K. Murphy,et al.  Regulation of interleukin 12 p40 expression through an NF-kappa B half-site , 1995, Molecular and cellular biology.

[3]  M. Wegner,et al.  IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas. , 2008, Cytokine.

[4]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[5]  Giorgio,et al.  Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells , 1992, The Journal of experimental medicine.

[6]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB , 2005, Nature Medicine.

[7]  K. Uysal,et al.  Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. , 1997, Nature.

[8]  T. Kooistra,et al.  Cytokines and atherosclerosis: a comprehensive review of studies in mice , 2008, Cardiovascular research.

[9]  M. Lindberg,et al.  Adipose Tissue , 2018 .

[10]  G. Baffy.  Kupffer cells in non-alcoholic fatty liver disease: the emerging view. , 2009, Journal of hepatology.

[11]  A. Yoshimura,et al.  Innate Defense Mechanism Against Virus Infection Within the Cardiac Myocyte Requiring gp130-STAT3 Signaling , 2006, Circulation.

[12]  R. Kastelein,et al.  Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. , 2007, Annual review of immunology.

[13]  T. Gill,et al.  Obesity: epidemiology and possible prevention. , 2002, Best practice & research. Clinical endocrinology & metabolism.

[14]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[15]  Michael Karin,et al.  A central role for JNK in obesity and insulin resistance , 2002, Nature.

[16]  G. Hotamisligil,et al.  Nutrient sensing and inflammation in metabolic diseases , 2008, Nature Reviews Immunology.

[17]  C. Hunter.  New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions , 2005, Nature Reviews Immunology.

[18]  V. Mohan,et al.  Increased levels of both Th1 and Th2 cytokines in subjects with metabolic syndrome (CURES-103). , 2011, Diabetes technology & therapeutics.

[19]  G. Trinchieri,et al.  Interleukin-12 and the regulation of innate resistance and adaptive immunity , 2003, Nature Reviews Immunology.

[20]  H. Green,et al.  The activation of specific gene transcription in the adipose conversion of 3T3 cells , 1985, Journal of cellular physiology.

[21]  M. Kagnoff,et al.  Expression of Epstein–Barr virus‐induced gene 3 and other interleukin‐12‐related molecules by human intestinal epithelium , 2004, Immunology.

[22]  E. Benveniste,et al.  IL‐27 inhibits OSM‐mediated TNF‐α and iNOS gene expression in microglia , 2010, Glia.

[23]  E. Maury,et al.  In vitro hyperresponsiveness to tumor necrosis factor-alpha contributes to adipokine dysregulation in omental adipocytes of obese subjects. , 2009, The Journal of clinical endocrinology and metabolism.

[24]  D. Vignali,et al.  Interleukin‐35: odd one out or part of the family? , 2008, Immunological reviews.

[25]  T. Mak,et al.  Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis1 , 2004, The Journal of Immunology.

[26]  Mitchell J. Anderson,et al.  Interleukin-6 and tumor necrosis factor-α are not increased in patients with Type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness , 2004, Diabetologia.

[27]  D. Merberg,et al.  Sequence similarity between NKSF and the IL-6/G-CSF family. , 1992, Immunology today.

[28]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[29]  C. Beadling,et al.  Regulation of innate and adaptive immune responses by the related cytokines IL-12, IL-23, and IL-27 , 2006, Archivum Immunologiae et Therapiae Experimentalis.

[30]  T. Mak,et al.  WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. , 2003, Immunity.

[31]  H. Yoshida,et al.  Regulation of immune responses by interleukin‐27 , 2008, Immunological reviews.

[32]  武田 篤信.  Cutting edge : Role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment , 2003 .

[33]  Jiali Gu,et al.  Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages. , 2006, Endocrinology.

[34]  A. Attie,et al.  Physiological insights gained from gene expression analysis in obesity and diabetes. , 2010, Annual review of nutrition.

[35]  R. Hopkins,et al.  Impact of Reference Gene Selection for Target Gene Normalization on Experimental Outcome Using Real-Time qRT-PCR in Adipocytes , 2010, PloS one.

[36]  B. Spiegelman,et al.  Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. , 1987, Science.

[37]  T. Yoshimoto,et al.  Regulation of Antitumor Immune Responses by the IL-12 Family Cytokines, IL-12, IL-23, and IL-27 , 2010, Clinical & developmental immunology.

[38]  D. Loskutoff,et al.  Monocyte chemoattractant protein 1 in obesity and insulin resistance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  D. Salamon,et al.  Increased interleukin-12 plasma concentrations in both, insulin-dependent and non-insulin-dependent diabetes mellitus , 1998, Diabetologia.

[40]  R. Morrison,et al.  Role of PPARγ in Regulating a Cascade Expression of Cyclin-dependent Kinase Inhibitors, p18(INK4c) and p21(Waf1/Cip1), during Adipogenesis* , 1999, The Journal of Biological Chemistry.

[41]  W. James,et al.  Effect of Plain Versus Sugar‐Sweetened Breakfast on Energy Balance and Metabolic Health: A Randomized Crossover Trial , 2020, Obesity.

[42]  M. Czech,et al.  Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes , 2008, Nature Reviews Molecular Cell Biology.

[43]  S. Schinner,et al.  Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications , 2009 .

[44]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. , 2005, Nature medicine.

[45]  M. Goldman,et al.  Interleukin-12 family members and the balance between rejection and tolerance , 2008, Current opinion in organ transplantation.

[46]  S. Tangye,et al.  Inflammatory Mechanisms in Obesity , 2013 .

[47]  K. Strissel,et al.  Dynamic, M2-Like Remodeling Phenotypes of CD11c+ Adipose Tissue Macrophages During High-Fat Diet–Induced Obesity in Mice , 2010, Diabetes.

[48]  D. Ouwens,et al.  The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease , 2010, Journal of cellular and molecular medicine.

[49]  B. Spiegelman,et al.  Reduced adipsin mRNA and circulating adipsin protein are modulated by adrenal steroids in obese Zucker rats. , 1990, The American journal of physiology.

[50]  K. Uysal,et al.  Protection from obesity-induced insulin resistance in mice lacking TNF-α function , 1997, Nature.