Obesity is the most common and powerful force for creating insulin resistance and metabolic syndrome, however, the molecular basis of this association is not well understood. In this proposal, three independently funded researchers-Philip Kern, MD a clinical investigator, and Charlotte Peterson, PhD and Robert McGehee, PhD, with significant experience in muscle and adipocyte biology, respectively-will formalize a collaborative effort as a natural extension of previous work and shared interests in the fields of obesity, insulin resistance, and tissue lipid accumulation. Our overall hypothesis is that insulin resistance in humans stems largely from ectopic accumulation of intramyocellular lipid (IMCL) during the development of obesity. Further, we hypothesize that excess IMCL accumulation is dependent on secretary proteins derived from a complex interplay between adipocytes and macrophages in adipose tissue. To test these hypotheses, we will examine the interactions among adipocytes, macrophages, and muscle cells isolated and cultured from subjects that are moderately obese with insulin resistance and impaired glucose tolerance (IGT), but who do not yet have fasting hyperglycemia. This study population has elevated IMCL and is at high risk for obesity complications, but avoids the pathophysiologic complications of glucotoxicity. These subjects will be compared to moderately obese subjects with normal glucose tolerance (NOT).
Aim 1 will explore mechanisms that contribute to IMCL and elucidate its role in the development of IGT. Cultured muscle cells will be used to determine whether obese subjects with IGT versus NGT demonstrate intrinsic differences in muscle gene expression and metabolic activity under differing extracellular fatty acid concentrations. Lipid accumulation and oxidation, and insulin-mediated glycogen synthesis and signaling will be assessed.
Aim 2 will determine if the IMCL accumulation is dependent on adipose tissue secretary proteins. We will use co-cultures of adipocytes, myoblasts, and adipose stromal vascular cells to examine IMCL and the development of insulin resistance.
Aim 3 will determine whether the stromal fraction from IGT subjects promotes IMCL more effectively than that from NGT subjects in co-cultures with muscle cells. We will compare the stromal vascular fractions with regard to monocyte/macrophage accumulation and cytokine expression.
Aim 4 will determine if improved glucose tolerance in response to a 10- week treatment with pioglitazone results in decreased IMCL and identify cellular mechanisms involved. Coculture studies will also be used with muscle and stromal cells, before and after pioglitazone treatment. These experiments will provide mechanistic insight into the link between obesity and muscle function leading to metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK071349-03
Application #
7258566
Study Section
Special Emphasis Panel (ZDK1-GRB-N (J2))
Program Officer
Laughlin, Maren R
Project Start
2005-06-01
Project End
2009-05-31
Budget Start
2006-07-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$178,822
Indirect Cost
Name
University of Kentucky
Department
Administration
Type
Schools of Public Health
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lawler, Helen M; Underkofler, Chantal M; Kern, Philip A et al. (2016) Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects. J Clin Endocrinol Metab 101:1422-8
Helsley, Robert N; Sui, Yipeng; Park, Se-Hyung et al. (2016) Targeting I?B kinase ? in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions. Stem Cells 34:1883-95
Park, Se-Hyung; Liu, Zun; Sui, Yipeng et al. (2016) IKK? Is Essential for Adipocyte Survival and Adaptive Adipose Remodeling in Obesity. Diabetes 65:1616-29
Kirby, Tyler J; Walton, R Grace; Finlin, Brian et al. (2016) Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue. Physiol Genomics 48:145-53
Walton, R Grace; Zhu, Beibei; Unal, Resat et al. (2015) Increasing adipocyte lipoprotein lipase improves glucose metabolism in high fat diet-induced obesity. J Biol Chem 290:11547-56
Spencer, Michael; Yang, Lin; Adu, Akosua et al. (2014) Pioglitazone treatment reduces adipose tissue inflammation through reduction of mast cell and macrophage number and by improving vascularity. PLoS One 9:e102190
Hodakoski, Cindy; Hopkins, Benjamin D; Barrows, Douglas et al. (2014) Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis. Proc Natl Acad Sci U S A 111:155-60
Fry, Christopher S; Noehren, Brian; Mula, Jyothi et al. (2014) Fibre type-specific satellite cell response to aerobic training in sedentary adults. J Physiol 592:2625-35
Kern, Philip A; Finlin, Brian S; Zhu, Beibei et al. (2014) The effects of temperature and seasons on subcutaneous white adipose tissue in humans: evidence for thermogenic gene induction. J Clin Endocrinol Metab 99:E2772-9
Ma, Lijun; Murea, Mariana; Snipes, James A et al. (2013) An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects. PLoS One 8:e56193

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