Genomes and Genes
The Role of PPAR-gamma Expression on Insulin Action
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
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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...
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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 ERα expression in hematopoietic/myeloid cells promotes aspects of the metabolic syndrome and accelerates atherosclerosis in female mice...
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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...
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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...
- Pigment epithelium-derived factor contributes to insulin resistance in obesitySeamus 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...
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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...
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University of California, Department of Cellular Molecular Medicine, La Jolla, San Diego, California 92093, USA
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Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
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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...
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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...
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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...
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Signal Transduction Program, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
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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...