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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK060484-05
Application #
7012745
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2002-02-15
Project End
2007-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$108,000
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Zhou, Zhenqi; Ribas, Vicent; Rajbhandari, Prashant et al. (2018) Estrogen receptor ? protects pancreatic ?-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J Biol Chem 293:4735-4751
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
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
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
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
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
Chung, Jason; Nguyen, Anh-Khoi; Henstridge, Darren C et al. (2008) HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A 105:1739-44
Pascual, Gabriel; Ricote, Mercedes; Hevener, Andrea L (2007) Macrophage peroxisome proliferator activated receptor gamma as a therapeutic target to combat Type 2 diabetes. Expert Opin Ther Targets 11:1503-20

Showing the most recent 10 out of 19 publications