INSULIN SIGNALING DEFECTS IN PCOS

Summary

Principal Investigator: Ricardo Azziz
Abstract: DESCRIPTION (provided by applicant): This application represents a competitive revision to R01-DK073632 'Insulin Signaling Defects in PCOS'and is being submitted in response to Notice NOT-OD-09-058 'NIH announces the availability of Recovery Act Funds for Competitive Revision Applications'. Insulin resistance occurs in ~70% of women with PCOS, which our data suggest may result from alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade, downstream of the insulin receptor (IR). PCOS adipocytes exhibit defective glucose transport, which may result from the altered phosphorylation of glycogen synthase kinase-3 (GSK3) we identified in PCOS. In our parent grant, we proposed to determine the contribution of abnormal GSK3 activity to defects in IR signaling and glucose transport, and to determine whether abnormal insulin signaling affecting the IRS/PI3-kinase/Akt cascade, occurs in PCOS adipocytes. During the course of our studies, we began to use microarray analysis to identify molecular mechanisms and signaling cascades potentially involved in insulin resistance in PCOS. We found that genes that inhibit the Wnt signaling pathway, upstream of GSK3, are up-regulated in PCOS adipose tissue, suggesting that decreased Wnt signaling may underlie the increased GSK activity in PCOS adipocytes. We also found alterations in the expression of components of JAK/STAT and MAPK pathways in PCOS adipose tissue. Both of these pathways mediate signaling by IL-6, a proinflammatory cytokine which we have found to decrease glucose transport specifically in PCOS adipocytes. Both Wnt and IL-6 also affect adipogenesis, defects of which have been found to increase insulin resistence. In this competitive revision, we propose to determine the effects of altered Wnt signaling of IL-6 signaling via the MAPK pathway, on adipogenesis, glucose transport and the PI3K/Akt insulin signaling pathway in PCOS vs. control adipocytes. Pursuing these avenues of investigation, which represent natural extensions of the scope of the parent grant, will yield valuable insights into the mechanisms and pathways underlying insulin resistance in PCOS. These studies will require the hiring of additional staff, as well as the purchase of a new microscope to study adipogenesis. PUBLIC HEALTH RELEVANCE: This revision meets the objectives of the Recovery Act by: enabling the hiring of additional staff;avoiding layoff of key personnel;and enabling the purchase of additional needed equipment. Moreover, we anticipate that by advancing the rate of our existing research, the supplement will enable us to lay the foundations for future submissions, which has the potential to both secure existing jobs and create new ones
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Preliminary evidence of glycogen synthase kinase 3 beta as a genetic determinant of polycystic ovary syndrome
    Mark O Goodarzi
    Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    Fertil Steril 87:1473-6. 2007
  2. pmc miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance
    Yen Hao Chen
    Department of Obstetrics Gynecology, Georgia Regents University, Augusta, Georgia, USA
    Diabetes 62:2278-86. 2013
  3. pmc Effects of endogenous androgens and abdominal fat distribution on the interrelationship between insulin and non-insulin-mediated glucose uptake in females
    Uche Ezeh
    Department of Obstetrics and Gynecology and Center for Androgen Related Disorders, Cedars SinaiMedical Center, Los Angeles, CA 90048, USA
    J Clin Endocrinol Metab 98:1541-8. 2013
  4. pmc Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome
    Uche Ezeh
    Department of Obstetrics and Gynecology, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Clin Endocrinol Metab 98:E1088-96. 2013
  5. pmc Ovarian and adipose tissue dysfunction in polycystic ovary syndrome: report of the 4th special scientific meeting of the Androgen Excess and PCOS Society
    Bulent O Yildiz
    Hacettepe University School of Medicine, Ankara, Turkey
    Fertil Steril 94:690-3. 2010
  6. pmc Adipocytes from women with polycystic ovary syndrome demonstrate altered phosphorylation and activity of glycogen synthase kinase 3
    Wendy Chang
    Department of Obstetrics and Gynecology, Division of Endocrinology, Diabetes and Metabolism, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    Fertil Steril 90:2291-7. 2008
  7. pmc Polycystic ovary syndrome: an ancient disorder?
    Ricardo Azziz
    Department of Obstetrics and Gynecology, Cedars Sinai Medical Center, Los Angeles, California, USA
    Fertil Steril 95:1544-8. 2011
  8. pmc Regulation of adiponectin secretion by adipocytes in the polycystic ovary syndrome: role of tumor necrosis factor-{alpha}
    Gregorio Chazenbalk
    Department of Obstetrics and Gynecology and Center for Androgen Related Disorders, Cedars Sinai Medical Center, 8635 West Third Street, Suite 160W, Los Angeles, California 90048, USA
    J Clin Endocrinol Metab 95:935-42. 2010
  9. pmc Abnormal expression of genes involved in inflammation, lipid metabolism, and Wnt signaling in the adipose tissue of polycystic ovary syndrome
    Gregorio Chazenbalk
    Department of Obstetrics Gynecology, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Clin Endocrinol Metab 97:E765-70. 2012
  10. pmc Novel pathway of adipogenesis through cross-talk between adipose tissue macrophages, adipose stem cells and adipocytes: evidence of cell plasticity
    Gregorio Chazenbalk
    Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America
    PLoS ONE 6:e17834. 2011

Scientific Experts

  • Gregorio Chazenbalk
  • Ricardo Azziz
  • Uche Ezeh
  • Bulent O Yildiz
  • Marita Pall
  • Mark O Goodarzi
  • Yen Hao Chen
  • Wendy Chang
  • Bo Shiun Chen
  • Ruchi Mathur
  • David W Stepp
  • Damini Dey
  • Daniel A Dumesic
  • Daniel Berman
  • Lawrence C Layman
  • Gloria Mabel Gamboa
  • Jung Min Lee
  • Saleh Heneidi
  • Ida Y Chen
  • Denis A Magoffin
  • Heith Williams
  • Jinrui Cui
  • Xiuqing Guo
  • Heath J Antoine

Detail Information

Publications10

  1. pmc Preliminary evidence of glycogen synthase kinase 3 beta as a genetic determinant of polycystic ovary syndrome
    Mark O Goodarzi
    Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    Fertil Steril 87:1473-6. 2007
    ..In each racial group, we observed that a specific, although different, GSK3B haplotype was associated with increased frequency of PCOS, suggesting that GSK3beta contributes to the pathophysiology and inherited basis of PCOS...
  2. pmc miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance
    Yen Hao Chen
    Department of Obstetrics Gynecology, Georgia Regents University, Augusta, Georgia, USA
    Diabetes 62:2278-86. 2013
    ..In contrast, miR-133 and miR-223 may have a different, although yet to be defined, role in the IR of PCOS. ..
  3. pmc Effects of endogenous androgens and abdominal fat distribution on the interrelationship between insulin and non-insulin-mediated glucose uptake in females
    Uche Ezeh
    Department of Obstetrics and Gynecology and Center for Androgen Related Disorders, Cedars SinaiMedical Center, Los Angeles, CA 90048, USA
    J Clin Endocrinol Metab 98:1541-8. 2013
    ..It is unknown whether in PCOS NIMGU increases to compensate for declining IMGU and whether androgens and fat distribution influence this relationship...
  4. pmc Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome
    Uche Ezeh
    Department of Obstetrics and Gynecology, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Clin Endocrinol Metab 98:E1088-96. 2013
    ..It is possible that the phenotype of PCOS would be different if the disorder were to be detected and studied in its natural (unbiased) state...
  5. pmc Ovarian and adipose tissue dysfunction in polycystic ovary syndrome: report of the 4th special scientific meeting of the Androgen Excess and PCOS Society
    Bulent O Yildiz
    Hacettepe University School of Medicine, Ankara, Turkey
    Fertil Steril 94:690-3. 2010
    ....
  6. pmc Adipocytes from women with polycystic ovary syndrome demonstrate altered phosphorylation and activity of glycogen synthase kinase 3
    Wendy Chang
    Department of Obstetrics and Gynecology, Division of Endocrinology, Diabetes and Metabolism, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    Fertil Steril 90:2291-7. 2008
    ..To test the hypothesis that an abnormality in glycogen synthase kinase-3 (GSK3) is a pathogenic factor in polycystic ovary syndrome (PCOS)...
  7. pmc Polycystic ovary syndrome: an ancient disorder?
    Ricardo Azziz
    Department of Obstetrics and Gynecology, Cedars Sinai Medical Center, Los Angeles, California, USA
    Fertil Steril 95:1544-8. 2011
    ..This raises the possibility that gene variants that are eventually found to be associated with PCOS will be similar across ethnic groups and races...
  8. pmc Regulation of adiponectin secretion by adipocytes in the polycystic ovary syndrome: role of tumor necrosis factor-{alpha}
    Gregorio Chazenbalk
    Department of Obstetrics and Gynecology and Center for Androgen Related Disorders, Cedars Sinai Medical Center, 8635 West Third Street, Suite 160W, Los Angeles, California 90048, USA
    J Clin Endocrinol Metab 95:935-42. 2010
    ..Adipose tissue dysfunction associated with low-grade chronic inflammation and dysregulation of adipokine secretion might significantly contribute to the pathogenesis of polycystic ovary syndrome (PCOS)...
  9. pmc Abnormal expression of genes involved in inflammation, lipid metabolism, and Wnt signaling in the adipose tissue of polycystic ovary syndrome
    Gregorio Chazenbalk
    Department of Obstetrics Gynecology, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Clin Endocrinol Metab 97:E765-70. 2012
    ..Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women...
  10. pmc Novel pathway of adipogenesis through cross-talk between adipose tissue macrophages, adipose stem cells and adipocytes: evidence of cell plasticity
    Gregorio Chazenbalk
    Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America
    PLoS ONE 6:e17834. 2011
    ..In the present study, using a novel co-culture system, we further characterized the interaction between ATMs, ASCs and adipocytes...