MAP Kinase Phosphatase 3 (MKP-3) and Obesity-related Gluconeogenesis

Summary

Principal Investigator: Haiyan Xu
Abstract: Obesity-related type 2 diabetes mellitus, characterized by insulin resistance, currently affects 150 million people worldwide. In the insulin resistant diabetic state, blood glucose levels are elevated due to increased glucose production from the liver (mainly through de novo glucose synthesis, gluconeogenesis) and decreased glucose disposal in fat and muscle. We recently identified MAP kinase phosphatase 3 (MKP- 3) as the top candidate for antagonizing the repressive effect of insulin on liver gluconeogenesis. We demonstrated that expression of MKP-3 is elevated in the liver of obese mice and MKP-3 overexpression is sufficent to promote gluconeogenesis in hepatocytes and elevate fasting blood glucose levels in lean mice. Reduction of MKP-3 expression by RNA interference decreases gluconeogenesis in hepatocytes and lowers fasting blood glucose levels in obese mice. Although the only known substrate of MKP-3 is ERK and activation of the ERK pathway can partially repress gluconeogenic gene expression, disruption of ERK function can not reverse the repressive effect of insulin on gluconeogenesis. This indicates that MKP-3 attenuates insulin signaling through a novel mechanism. Forkhead transcription factor FOXO1, which can be activated through dephosphorylation that leads to consequent nuclear translocatin to initiate the gluconeogenic program, is a critical factor for insulin to repress glucose production. Our recent data indicate that MKP-3 interacts with FOXO1, synergizes with FOXO1 to transcribe PEPCK and G6Pase genes, decreases insulin stimulated FOXO1 phosphorylation and increases its nuclear translocation. Furthermore, overexpression of the dominant negative FOXO1 can block MKP-3 stimulated gluconeogenic gene expression and glucose in primary hepatocytes and nuclear FOXO1 is decreased by hepatic MKP-3 knockdown. Interestingly, the gluconeogenic effect of MKP-3 is dramatic in primary hepatocyes and mild in Fao cells, which are devoid of gluconeogenic amplifier PGC-11. Knocking down PGC-11 expression in primary hepatocytes essentially abolished the effect of MKP-3 on gluconeogenic gene expression and glucose output. We hypothesize that MKP-3 antagonizes the inhibitory effect of insulin on gluconeogenesis through activation of FOXO1 by dephosphorylation and PGC-11 is a critical co- activator. The specific aims are: 1) Define the role of FOXO1 in MKP-3-mediated gluconeogenesis;2) Modulate hepatic MKP-3 expression and evaluate the effect on gluconeogenesis and glycemic control;3) Understand the downstream target of MKP-3 promoted fasting hyperglycemia in vivo. The goals will be achieved through reporter assays and adenovirus-mediated gain and loss-of-function studies in cultured liver cells, primary liver cells and in the liver of normal as well as obese animals. Results generated from this proposal will provide key information to understand the mechanism of action of MKP-3 and evaluate its candidacy as a new therapeutic target for treating obesity-related type 2 diabetes. PUBLIC HEALTH RELEVANCE: Obesity-related type 2 diabetes, featured with decreased body response to insulin, is attributable to increased liver glucose production and decreased glucose utilization by muscle and fat. A novel factor was recently found to elevate in the liver of obese rodents, antagonize the action of insulin in the liver, promote liver glucose production and contribute significantly to hyperglycemia in obesity. Results generated from research outlined in this proposal will provide key information to understand the mechanism of action of this protein and evaluate its candidacy as a new therapeutic target for treating obesity-related type 2 diabetes.
Funding Period: 2009-01-15 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice
    Zhidan Wu
    Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA
    J Clin Invest 120:3901-11. 2010
  2. pmc MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells
    Bin Feng
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
    Mol Cell Endocrinol 361:116-23. 2012
  3. pmc Mapping MKP-3/FOXO1 interaction and evaluating the effect on gluconeogenesis
    Ping Jiao
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America
    PLoS ONE 7:e41168. 2012
  4. pmc Human adipose dynamics and metabolic health
    Bin Feng
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
    Ann N Y Acad Sci 1281:160-77. 2013
  5. pmc Identification of sucrose non-fermenting-related kinase (SNRK) as a suppressor of adipocyte inflammation
    Yujie Li
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
    Diabetes 62:2396-409. 2013
  6. pmc Hepatic ERK activity plays a role in energy metabolism
    Ping Jiao
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
    Mol Cell Endocrinol 375:157-66. 2013

Research Grants

Detail Information

Publications7

  1. pmc MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice
    Zhidan Wu
    Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA
    J Clin Invest 120:3901-11. 2010
    ..These data indicate that MKP-3 is an important regulator of hepatic gluconeogenesis in vivo and suggest that inhibition of MKP-3 activity may provide new therapies for T2DM...
  2. pmc MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells
    Bin Feng
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
    Mol Cell Endocrinol 361:116-23. 2012
    ..In conclusion, insulin likely promotes MKP-3 protein degradation through activation of MEK/ERK pathway in liver cells and MKP-3 protein level affects the capability of Fao cells to output glucose...
  3. pmc Mapping MKP-3/FOXO1 interaction and evaluating the effect on gluconeogenesis
    Ping Jiao
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America
    PLoS ONE 7:e41168. 2012
    ..Reduction of hepatic MKP-3 expression is sufficient to reduce blood glucose levels in both diet-induced and genetically obese mice...
  4. pmc Human adipose dynamics and metabolic health
    Bin Feng
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
    Ann N Y Acad Sci 1281:160-77. 2013
    ..Therapeutic approaches targeting adipose tissue have been proven to be effective in improving obesity-related metabolic disorders, and promising new therapies could be developed in the near future...
  5. pmc Identification of sucrose non-fermenting-related kinase (SNRK) as a suppressor of adipocyte inflammation
    Yujie Li
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
    Diabetes 62:2396-409. 2013
    ..In summary, SNRK may act as a suppressor of adipocyte inflammation and its presence is necessary for maintaining normal adipocyte function. ..
  6. pmc Hepatic ERK activity plays a role in energy metabolism
    Ping Jiao
    Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
    Mol Cell Endocrinol 375:157-66. 2013
    ..These results indicate that increased hepatic ERK activity in DIO mice may contribute to increased liver glycogen content and decreased energy expenditure in obesity. ..

Research Grants30

  1. Atypical PKC Knockout Models: Effect on Glucose and Lipid Homeostasis
    Robert V Farese; Fiscal Year: 2013
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