The Role of PPAR-gamma Expression on Insulin Action

Summary

Principal Investigator: Andrea Hevener
Abstract: Insulin resistance is a characteristic feature of obesity and type 2 diabetes. The PPAR-gamma nuclear receptor is the target of Thiazolidinediones (TZDs), a class of anti-diabetic drugs known to ameliorate insulin resistance. Despite the known actions of TZDs to improve insulin sensitivity, many aspects of PPARgamma biology remain unclear. In overview, we propose to delineate the tissue specific roles of PPARgamma expression in skeletal muscle, macrophage, and adipose tissue with respect to glucose tolerance and insulin sensitivity. We have previously shown that mice heterozygous for the PPARgamma null allele (whole body) display heightened insulin sensitivity. To identify the tissue(s) responsible for conferring this heightened insulin sensitivity phenotype, we have employed the Cre-Lox system to create PPARgamma tissue specific heterozygous mice. In addition we will use these tissue specific heterozygote mice to further characterize the role of PPARgamma in 1) the regulation of NF-kappaB inflammatory pathway activation, and 2) tissue specific macrophage recruitment/activation as it relates to the pathogenesis of insulin resistance. To assess the importance of macrophage PPARgamma expression on monocyte/macrophage activation and recruitment to metabolically impaired tissues, we will withdraw bone marrow from macrophage PPARgamma null mice (MX-KO) and transplant these cells into normal wild type C57 black recipient mice (BMT). Bone marrow recipient animals, BMT:MX-KO and control WT mice will be placed on a high fat diet known to cause skeletal muscle and adipose tissue insulin resistance. We will assess whole body insulin sensitivity (glucose clamp technique) and glucose tolerance in transplanted and non-transplanted mice and correlate these findings to macrophage infiltration, activation, and tissue as well as circulating cytokine/adipokine levels. Findings from these proposed studies will provide critical information to improve our mechanistic understanding and treatment of insulin resistance and diabetes.
Funding Period: 2002-02-15 - 2007-01-31
more information: NIH RePORT

Top Publications

  1. pmc Sarcopenia exacerbates obesity-associated insulin resistance and dysglycemia: findings from the National Health and Nutrition Examination Survey III
    Preethi Srikanthan
    Division of Gerontology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
    PLoS ONE 5:e10805. 2010
  2. pmc Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development
    Vicent Ribas
    David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, CA 90095 7073, USA
    Proc Natl Acad Sci U S A 108:16457-62. 2011
  3. pmc Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice
    Vicent Ribas
    David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, University of California Los Angeles, Los Angeles, California 90095 7073, USA
    Am J Physiol Endocrinol Metab 298:E304-19. 2010
  4. pmc Hypermetabolism, hyperphagia, and reduced adiposity in tankyrase-deficient mice
    Tsung Yin J Yeh
    Department of Medicine, Endocrine Division, University of California, San Diego, La Jolla, California, USA
    Diabetes 58:2476-85. 2009
  5. ncbi Pigment epithelium-derived factor contributes to insulin resistance in obesity
    Seamus Crowe
    Department of Physiology, Monash University, Clayton, Victoria 3800, Australia
    Cell Metab 10:40-7. 2009
  6. pmc HSP72 protects against obesity-induced insulin resistance
    Jason Chung
    Cellular and Molecular Metabolism Laboratory, Clinical Physiology, and Human Vascular Biology, Baker Heart Research Institute, Prahran, P O Box 6492, Victoria 8008, Australia
    Proc Natl Acad Sci U S A 105:1739-44. 2008
  7. ncbi Macrophage peroxisome proliferator activated receptor gamma as a therapeutic target to combat Type 2 diabetes
    Gabriel Pascual
    University of California, Department of Cellular Molecular Medicine, La Jolla, San Diego, California 92093, USA
    Expert Opin Ther Targets 11:1503-20. 2007
  8. ncbi Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver
    Mara Monetti
    Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
    Cell Metab 6:69-78. 2007
  9. pmc Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones
    Andrea L Hevener
    Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA
    J Clin Invest 117:1658-69. 2007
  10. ncbi Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance
    Mark K Todd
    Department of Kinesiology, University of Southern California, Los Angeles, California, USA
    Am J Physiol Endocrinol Metab 292:E485-93. 2007

Scientific Experts

  • Andrea Hevener
  • Matthew J Watt
  • Vicent Ribas
  • Darren C Henstridge
  • Preethi Srikanthan
  • Mark A Febbraio
  • Anh Khoi Nguyen
  • Seamus Crowe
  • Tsung Yin J Yeh
  • Jason Chung
  • Mara Monetti
  • Gabriel Pascual
  • Mark K Todd
  • Melek C Arkan
  • Emilie A Bard-Chapeau
  • Jamie A Le
  • Steven J Bensinger
  • Teo Soleymani
  • Kenneth S Korach
  • Pedram Daraei
  • Daniel Sitz
  • Sylvia C Hewitt
  • Laila Mohammad
  • Brian G Drew
  • Simon W Beaven
  • M T Audrey Nguyen
  • Arun S Karlamangla
  • Maria Matzaris
  • Pingping Li
  • Ray M Lee
  • Sarah M Turpin
  • Kyle L Hoehn
  • Nai Wen Chi
  • Anne N Murphy
  • Elia J Duh
  • Kristina K Beiswenger
  • Catherine Economou
  • David E James
  • Tsu Shuen Tsao
  • Lindsay E Wu
  • Krista E Bolin
  • Bronwyn A Kingwell
  • Clinton R Bruce
  • Laszlo Vigh
  • Graeme I Lancaster
  • Jose L Mesa
  • Stephen J Duffy
  • Philip L Hooper
  • Ruben Mestril
  • M H Stanley Chan
  • Anna G Holmes
  • Robert J Southgate
  • Ibolya Horvath
  • Lorraine P Turcotte
  • Mini P Sajan
  • Stephen Marmor
  • Christopher B Newgard
  • James R Bain
  • Mercedes Ricote
  • Robert V Farese
  • Jamie Le
  • Brian K Hubbard
  • Malin C Levin
  • Robert D Stevens
  • Gen Sheng Feng
  • Shinong Long
  • Jerrold Olefsky
  • Jeffrey M Long
  • Jerrold M Olefsky
  • Zhi Wei Li
  • Eric E Zhang
  • Anthony Wynshaw-Boris
  • Giuseppe Poli
  • Michael Karin
  • Florian R Greten
  • Shin Maeda

Detail Information

Publications13

  1. pmc Sarcopenia exacerbates obesity-associated insulin resistance and dysglycemia: findings from the National Health and Nutrition Examination Survey III
    Preethi Srikanthan
    Division of Gerontology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
    PLoS ONE 5:e10805. 2010
    ..We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals...
  2. pmc Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development
    Vicent Ribas
    David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, CA 90095 7073, USA
    Proc Natl Acad Sci U S A 108:16457-62. 2011
    ..Our findings suggest that diminished ERĪ± expression in hematopoietic/myeloid cells promotes aspects of the metabolic syndrome and accelerates atherosclerosis in female mice...
  3. pmc Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice
    Vicent Ribas
    David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, University of California Los Angeles, Los Angeles, California 90095 7073, USA
    Am J Physiol Endocrinol Metab 298:E304-19. 2010
    ..These data indicate that ERalpha is critical for the maintenance of whole body insulin action and protection against tissue inflammation during both normal chow and high-fat feeding...
  4. pmc Hypermetabolism, hyperphagia, and reduced adiposity in tankyrase-deficient mice
    Tsung Yin J Yeh
    Department of Medicine, Endocrine Division, University of California, San Diego, La Jolla, California, USA
    Diabetes 58:2476-85. 2009
    ..Its chromosomal locus 8p23.1 is linked to monogenic forms of diabetes in certain kindred. We hypothesize that TNKS is involved in energy homeostasis in mammals...
  5. ncbi Pigment epithelium-derived factor contributes to insulin resistance in obesity
    Seamus Crowe
    Department of Physiology, Monash University, Clayton, Victoria 3800, Australia
    Cell Metab 10:40-7. 2009
    ..Overall, these results identify a causal role for PEDF in obesity-induced insulin resistance...
  6. pmc HSP72 protects against obesity-induced insulin resistance
    Jason Chung
    Cellular and Molecular Metabolism Laboratory, Clinical Physiology, and Human Vascular Biology, Baker Heart Research Institute, Prahran, P O Box 6492, Victoria 8008, Australia
    Proc Natl Acad Sci U S A 105:1739-44. 2008
    ..These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding...
  7. ncbi Macrophage peroxisome proliferator activated receptor gamma as a therapeutic target to combat Type 2 diabetes
    Gabriel Pascual
    University of California, Department of Cellular Molecular Medicine, La Jolla, San Diego, California 92093, USA
    Expert Opin Ther Targets 11:1503-20. 2007
    ....
  8. ncbi Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver
    Mara Monetti
    Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
    Cell Metab 6:69-78. 2007
    ..Our results indicate that DGAT-mediated lipid accumulation in the liver is insufficient to cause insulin resistance and show that hepatic steatosis can occur independently of insulin resistance...
  9. pmc Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones
    Andrea L Hevener
    Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA
    J Clin Invest 117:1658-69. 2007
    ..These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs...
  10. ncbi Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance
    Mark K Todd
    Department of Kinesiology, University of Southern California, Los Angeles, California, USA
    Am J Physiol Endocrinol Metab 292:E485-93. 2007
    ..Despite this, TZDs suppress the inflammatory response to dietary lipid overload, and it is this mechanism that correlates strongly with insulin sensitivity...
  11. ncbi Ciliary neurotrophic factor prevents acute lipid-induced insulin resistance by attenuating ceramide accumulation and phosphorylation of c-Jun N-terminal kinase in peripheral tissues
    Matthew J Watt
    Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia
    Endocrinology 147:2077-85. 2006
    ..These data support the use of CNTF as a potential therapeutic means to combat lipid-induced insulin resistance...
  12. ncbi Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action
    Emilie A Bard-Chapeau
    Signal Transduction Program, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
    Nat Med 11:567-71. 2005
    ..Thus, Gab1 acts to attenuate, through promotion of the Erk pathway, insulin-elicited signals flowing through IRS and Akt proteins, which represents a novel balancing mechanism for control of insulin signal strength in the liver...
  13. ncbi IKK-beta links inflammation to obesity-induced insulin resistance
    Melek C Arkan
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
    Nat Med 11:191-8. 2005
    ..We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance...