Mechanisms of Brd2 immunoprotection from insulin resistance

Summary

Principal Investigator: Gerald V Denis
Abstract: Modern high calorie diets and reduced physical activity promote obesity, which has become an alarming public health concern. The wide-ranging, health-related impacts of obesity include cardiovascular disease, metabolic syndrome, non-alcoholic fatty liver disease, some forms of cancer, and Type 2 diabetes in particular, which is a disorder of insulin production and action that has life-threatening consequences. The worsening problem of obesity predicts that these co-morbidities will strain or break health care delivery systems worldwide. It is a matter of some urgency that the genes that couple obesity to these diseases remain incompletely understood. However, it has been appreciated for some time that certain obese individuals are at reduced risk for cardiovascular disease and Type 2 diabetes. These [unreadable]metabolically healthy but obese[unreadable] (MHO) patients are important because of the opportunity they provide to increase our understanding of the etiology of obesitydriven diabetes. We have recently published our finding that a dual bromodomain protein and transcriptional co-activator called Brd2 is an unexpected yet important regulator of obesity and glucose homeostasis. Mice deficient for Brd2 develop extraordinary obesity with body weights approaching 100g, but never develop insulin resistance (IR) or Type 2 diabetes, suggesting that they offer a unique animal model for these MHO patients. Like MHO patients, Brd2-deficient mice show reduced inflammatory processes, which we hypothesize protect them from IR. Their white adipose tissue (WAT) is not infiltrated by inflammatory macrophages, and bone marrow-derived macrophages underproduce pro-inflammatory cytokines. Interestingly, Brd2 ordinarily binds to PPAR-gamma and opposes its transcriptional activity, thus, Brd2 deficiency resembles thiazolidinedione action. Thiazolidinediones are insulin-sensitizing drugs that act as agonists of PPAR-gamma. We hypothesize that PPAR-gamma-dependent processes, including adipogenesis and macrophage M2 polarization, are strongly potentiated in these mice. Preliminary gene expression profiling studies of human abdominal adipocytes establish that PPAR-gamma levels are negatively correlated with Brd2, matching the animal model and indicating functional conservation. Thus, studies of these mice are likely to be highly informative of novel, MHO-specific pathways that could be exploited to treat obese patients at serious risk for Type 2 diabetes. Based on these preliminary data we structure our approach in three Specific Aims: 1. Define cellular and molecular mechanisms by which Brd2 deficiency protects WAT against the pro-inflammatory (M1) phenotype of adipose tissue macrophages. 2. Use co-culture of macrophage and adipocyte models to determine whether Brd2 deficiency protects adipocytes from cytokine-driven IR or promotes M2 polarization of macrophages, or both. 3. Determine the mechanism of Brd2 transactivation of the TNF-alpha gene. The molecular insights we expect to attain will open new avenues for treatment of IR and metabolic syndrome, and will allow the intrinsic protections of MHO patients to be extended to the general population of obese and overweight individuals.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc The outliers become a stampede as immunometabolism reaches a tipping point
    Barbara S Nikolajczyk
    Department of Microbiology, Boston University, Boston, MA 02118, USA
    Immunol Rev 249:253-75. 2012
  2. pmc 'Metabolically healthy obesity': origins and implications
    Gerald V Denis
    Immunology Training Program, Cancer Research Center and Boston Nutrition Obesity Research Center, Boston University School of Medicine, 72 East Concord St Room K520, Boston, MA, USA
    Mol Aspects Med 34:59-70. 2013
  3. pmc Brd2 gene disruption causes "metabolically healthy" obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes
    Fangnian Wang
    IQuum Inc, Marlborough, MA 01752, USA
    Vitam Horm 91:49-75. 2013
  4. pmc BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses
    Anna C Belkina
    Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA
    J Immunol 190:3670-8. 2013
  5. pmc B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile
    Jason DeFuria
    Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA
    Proc Natl Acad Sci U S A 110:5133-8. 2013
  6. pmc Healthy obese persons: how can they be identified and do metabolic profiles stratify risk?
    Gerald V Denis
    Cancer Research Center and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    Curr Opin Endocrinol Diabetes Obes 20:369-76. 2013
  7. pmc The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis
    Anna C Belkina
    1 72 East Concord St, Rm K520, Boston, MA 02118, USA Twitter http www twitter com GdenisBoston
    J Leukoc Biol 95:451-60. 2014

Detail Information

Publications7

  1. pmc The outliers become a stampede as immunometabolism reaches a tipping point
    Barbara S Nikolajczyk
    Department of Microbiology, Boston University, Boston, MA 02118, USA
    Immunol Rev 249:253-75. 2012
    ....
  2. pmc 'Metabolically healthy obesity': origins and implications
    Gerald V Denis
    Immunology Training Program, Cancer Research Center and Boston Nutrition Obesity Research Center, Boston University School of Medicine, 72 East Concord St Room K520, Boston, MA, USA
    Mol Aspects Med 34:59-70. 2013
    ....
  3. pmc Brd2 gene disruption causes "metabolically healthy" obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes
    Fangnian Wang
    IQuum Inc, Marlborough, MA 01752, USA
    Vitam Horm 91:49-75. 2013
    ....
  4. pmc BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses
    Anna C Belkina
    Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA
    J Immunol 190:3670-8. 2013
    ..We propose that targeting BET proteins with small-molecule inhibitors will benefit hyperinflammatory conditions associated with high levels of cytokine production...
  5. pmc B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile
    Jason DeFuria
    Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA
    Proc Natl Acad Sci U S A 110:5133-8. 2013
    ..Thus, B cells are potential therapeutic targets for T2D...
  6. pmc Healthy obese persons: how can they be identified and do metabolic profiles stratify risk?
    Gerald V Denis
    Cancer Research Center and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    Curr Opin Endocrinol Diabetes Obes 20:369-76. 2013
    ..Although weight loss is appreciated to improve metabolic and inflammatory parameters, the cellular and immune factors that couple obesity to cardiometabolic risk are only partially understood...
  7. pmc The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis
    Anna C Belkina
    1 72 East Concord St, Rm K520, Boston, MA 02118, USA Twitter http www twitter com GdenisBoston
    J Leukoc Biol 95:451-60. 2014
    ..Brd2-specific knockdown experiments show that Brd2 is also required for hematopoiesis. We conclude that Brd2 plays a critical, independent role in regulation of mitogenic response genes, particularly cyclin A, in B cells. ..