A2b Adenosine Receptor Regulation of Metabolic Disease and Inflammation

Summary

Principal Investigator: Anna Eisenstein
Abstract: DESCRIPTION (provided by applicant): Type II diabetes mellitus (T2D) is a major risk factor for multiple diseases and a significant contributor to morbidity and mortality in the United States T2D is defined by an inability of the body to respond to changing blood glucose levels due to reduced responsiveness of tissues to the glucose regulatory hormone, insulin, and/or an insufficient secretion of insulin. Obesity, a significant risk factor for T2D, is associated with chronic inflammation and it has become clear that inflammation can contribute to insulin resistance. The macrophage is a key mediator of obesity-induced inflammation. However, the mechanism connecting obesity, inflammation and T2D is not clearly established. One interesting signaling molecule that may play a role in this triad is adenosine, a metabolite that is elevated following cellular stress and inflammation. Adenosine signaling through the A2b adenosine receptor (A2bAR) has been shown to dampen the release of inflammatory cytokines. Furthermore, administration of a high fat, high cholesterol diet (HFD) vastly upregulates the expression of the A2b adenosine receptor (A2bAR), and A2bAR KO mice subjected to HFD have elevated plasma cytokine levels compared to wild type (WT) mice. Intriguingly, A2bAR KO mice also have delayed glucose clearance and augmented insulin levels following HFD. Adipose tissue and liver insulin signaling is reduced in A2bAR KO mice relative to WT mice. One important mediator of insulin signaling, the insulin receptor substrate 2 (IRS-2), is reduced by the action of inflammatory cytokines. In search for a mechanism of impaired glucose handling in A2bAR KO mice, the level of IRS-2 was shown to be decreased in the liver and adipose tissue of A2bAR KO mice. Importantly, pharmacological activation of A2bAR in WT mice (with an A2bAR ligand) fed a HFD restores IRS-2 levels and ameliorates T2D. Importantly, A2bAR expression is elevated in adipose tissue from obese human subjects as compared to lean subjects and A2bAR expression correlates strongly with IRS-2 expression. Considering the control of inflammatory cytokines by A2bAR, and the regulation of IRS-2 and insulin signaling by these cytokines, we hypothesize a link between macrophage A2bAR, adipose tissue inflammation, and insulin signaling. With access to genetically modified mice and to human adipose tissue from diabetic and non-diabetic obese individuals, this proposal will examine the novel contentions that metabolically healthy adipose tissue from obese humans have a strong expression of A2bAR and IRS-2 as compared to metabolically unhealthy obese humans (Aim 1), and that fat and/or macrophage A2bAR signaling contributes to regulation of IRS-2 and to glucose homeostasis (Aim 2). Proposed studies might open new receptor-based therapeutic approaches, facilitated by the collaboration and support of my co- mentors on this project, Dr. Ravid, a Biochemist and expert in vascular and adenosine biology, and Dr. Gokce, a Clinician Scientist with access to human samples and expertise in studying human adipose tissue.
Funding Period: 2013-06-01 - 2016-05-31
more information: NIH RePORT

Top Publications

  1. ncbi G protein-coupled receptors and adipogenesis: a focus on adenosine receptors
    Anna Eisenstein
    Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
    J Cell Physiol 229:414-21. 2014

Detail Information

Publications1

  1. ncbi G protein-coupled receptors and adipogenesis: a focus on adenosine receptors
    Anna Eisenstein
    Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
    J Cell Physiol 229:414-21. 2014
    ..This review will highlight GPCRs and their downstream messengers as significant players controlling adipocyte differentiation...

Research Grants30

  1. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  2. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  3. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  4. Defining Adaptive Immune Mechanisms of Insulin Resistance
    Edgar G Engleman; Fiscal Year: 2013
    ..The results of these experiments promise to yield new diagnostic and therapeutic modalities to manage this important disease. ..
  5. Atypical PKC Knockout Models: Effect on Glucose and Lipid Homeostasis
    Robert V Farese; Fiscal Year: 2013
    ..abstract_text> ..
  6. Genetic and physiological causes of inherited Vascular and Metabolic Diseases
    Arya Mani; Fiscal Year: 2013
    ..The current study goals are investigating the effect of the mutation on metabolism of glucose and insulin secretion and function in patients with this mutation. ..
  7. Study to Investigate the Pathophysiology of Type 2 Diabetes in Youth
    Sonia Caprio; Fiscal Year: 2013
    ....
  8. Macrophage AMPK, Inflammation, and Atherosclerosis
    Bingzhong Xue; Fiscal Year: 2013
    ..Completing these studies will greatly improve our knowledge on the role of macrophage AMPK in the protection against inflammation-associated metabolic disorders, including atherosclerosis and insulin resistance. ..
  9. Circadian Clock Disruption: A Mechanism for Dioxin-induced Metabolic Syndrome
    Shelley A Tischkau; Fiscal Year: 2013
    ..This proposal examines the novel hypothesis that dioxins exert their action through aryl hydrocarbon receptor-mediated uncoupling of homeostatic regulation of organismic circadian rhythms. ..
  10. Role of Chromogranin A in Metabolic Syndrome
    Sushil K Mahata; Fiscal Year: 2013
    ..2. Evaluate the potential therapeutic effects of CST and its variants on insulin sensitivity and baroreflex sensitivity and heart rate variability in high fat diet-induced insulin resistant and in db/db diabetic mice. ..
  11. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  12. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  13. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  14. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  15. Insulin Signaling and Metabolic Effects through CLK2 Kinase
    Pere Puigserver; Fiscal Year: 2013
    ....
  16. Adiponectin Actions on the Monocyte to Reduce Atherosclerosis
    Rajendra K Tangirala; Fiscal Year: 2013
    ..abstract_text> ..
  17. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  18. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..