Insulin resistance is an underlying cause of type 2 diabetes and a defining feature of the Metabolic Syndrome. We have shown that estrogen provides protection from metabolic and genetic perturbations known to cause insulin resistance in males and this protection is lost with age and coinciding with menopause. Similar to the effects of estrogen, PPAR-gamma (g) activation by thiazolidinediones (TZDs) causes insulin sensitization via alterations is transcription of genes involved in glucose and fatty acid metabolism as well as inflammation. We have previously shown that selective skeletal muscle PPAR-g deletion (MKO) causes glucose intolerance and severe insulin resistance in young and aged male mice. Surprisingly, preliminary studies in female MKO mice show that loss of skeletal muscle PPAR-g yields enhanced glucose tolerance and insulin sensitivity, a phenotype opposite of that described for males. Subsequently we have treated male MKO mice with a TZD or estradiol (E2), and while the TZD was without effect on skeletal muscle insulin sensitivity, E2 treatment caused increased insulin action above that observed for WT control mice which implicates a crosstalk between PPAR-g and the estrogen receptor.
In Aim 1, we will test the hypothesis that PPAR-g decreases ER action in skeletal muscle from estrogenized animals. We will assess insulin sensitivity in male and female mice treated with or without E2 in the presence (fl/fl Control) or absence of skeletal muscle PPAR-g (MKO).
In Aim 2 we will test the hypothesis that PPAR-g activation by Rosiglitazone diminishes the insulin sensitizing effects of E2 in female rats rendered insulin resistant by ovariectomy and or high fat diet. In both aims we will perform glucose clamp studies to assess insulin sensitivity complemented by in vitro studies to investigate the molecular mechanisms leading to phenotypic expression. To this end, Western blot and quantitative RT-PCR analyses will be performed on tissues harvested from clamped animals to assess alterations in insulin signal transduction and gene transcription in muscle and fat. These studies are of clinical importance for diabetic women of advanced age as the interaction of these agonists on gene transcription is unknown. Additionally our goal is to elucidate the importance of nuclear receptor crosstalk in the regulation of gene transcription and show that aberrant crosstalk is an underlying mechanism of insulin resistance and obesity. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21DK073227-02
Application #
7296110
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2006-09-30
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$186,918
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ribas, Vicent; Drew, Brian G; Zhou, Zhenqi et al. (2016) Skeletal muscle action of estrogen receptor ? is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci Transl Med 8:334ra54
Drew, Brian G; Hamidi, Habib; Zhou, Zhenqi et al. (2015) Estrogen receptor (ER)?-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. J Biol Chem 290:5566-81
Ribas, Vicent; Drew, Brian G; Le, Jamie A et al. (2011) Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci U S A 108:16457-62
Srikanthan, Preethi; Hevener, Andrea L; Karlamangla, Arun S (2010) Sarcopenia exacerbates obesity-associated insulin resistance and dysglycemia: findings from the National Health and Nutrition Examination Survey III. PLoS One 5:e10805
Sachithanandan, Nirupa; Fam, Barbara C; Fynch, Stacey et al. (2010) Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity. Hepatology 52:1632-42
Yamada, P M; Mehta, H H; Hwang, D et al. (2010) Evidence of a role for insulin-like growth factor binding protein (IGFBP)-3 in metabolic regulation. Endocrinology 151:5741-50
Ribas, Vicent; Nguyen, M T Audrey; Henstridge, Darren C et al. (2010) Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice. Am J Physiol Endocrinol Metab 298:E304-19
Yeh, Tsung-Yin J; Beiswenger, Kristina K; Li, Pingping et al. (2009) Hypermetabolism, hyperphagia, and reduced adiposity in tankyrase-deficient mice. Diabetes 58:2476-85
Turpin, S M; Ryall, J G; Southgate, R et al. (2009) Examination of 'lipotoxicity' in skeletal muscle of high-fat fed and ob/ob mice. J Physiol 587:1593-605
Crowe, Seamus; Wu, Lindsay E; Economou, Catherine et al. (2009) Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab 10:40-7

Showing the most recent 10 out of 13 publications