Increased flux of free fatty acids (FFA) from adipose tissue to non-adipose tissues contributes to and augments many metabolic derangements that are characteristic of the metabolic syndrome and type 2 diabetes, including insulin resistance. Evidence indicates that adipocyte mitochondria may play an important role in adipocyte FFA sequestration, suggesting that abnormalities of these organelles may contribute to an increased FFA flux from adipose tissue. Recent animal studies and very limited human studies have demonstrated various abnormalities of adipocyte mitochondria in insulin resistance and reversal of most of these abnormalities by treatment with thiazolidinediones (TZD), but FFA flux has not been determined. Therefore, the overall goal of this project is to examine whether abnormalities of adipocyte mitochondria are associated with increased FFA flux in humans, and hence contribute to its related metabolic derangements. We will address the following Specific Aims: 1) To examine mitochondrial mass and density of isolated adipocytes in subjects that are resistant to suppression of FFA release by insulin and subjects that are sensitive to the suppression of FFA release by insulin. We will test the hypothesis that adipocyte mitochondrial mass or density is reduced in individuals with resistance of systemic FFA release to suppression by insulin. 2) To use HPLC-ESI-MS/MS proteomics to determine the relative abundance of mitochondrial proteins in adipocytes from subjects that are resistant to suppression of FFA release by insulin and subjects that are sensitive to the suppression of FFA release by insulin. We will test the hypothesis that there are differences in adipocyte mitochondrial protein abundance in individuals with resistance of systemic FFA release to suppression by insulin regardless of mitochondrial mass/density. 3) To use polarographic analyses to determine, in the presence of different substrates, the respiratory capacity and the sensitivity of respiratory control to energy demand of isolated adipocyte mitochondria from subjects that are resistant to suppression of FFA release by insulin and subjects that are sensitive to the suppression of FFA release by insulin. We will test the hypothesis that there are functional abnormalities of adipocyte mitochondria in individuals with resistance of systemic FFA release to suppression by insulin that correspond to alterations in protein abundance. Better understanding of the mechanisms of increased flux of FFA from adipose tissue is critical for developing treatment and prevention strategies for conditions related to increased plasma FFA levels, including type 2 diabetes.

Public Health Relevance

Insulin resistance in skeletal muscle and liver plays a major role in the pathogenesis of impaired glucose tolerance and type 2 diabetes. Better understanding of the molecular mechanisms is critical for the development of therapeutic strategies and prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK082820-01A1
Application #
7739897
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
2009-08-05
Project End
2011-07-30
Budget Start
2009-08-05
Budget End
2010-07-30
Support Year
1
Fiscal Year
2009
Total Cost
$221,239
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Xie, X; Sinha, S; Yi, Z et al. (2017) Role of adipocyte mitochondria in inflammation, lipemia and insulin sensitivity in humans: effects of pioglitazone treatment. Int J Obes (Lond) :
Xie, Xitao; Yi, Zhengping; Sinha, Sandeep et al. (2016) Proteomics analyses of subcutaneous adipocytes reveal novel abnormalities in human insulin resistance. Obesity (Silver Spring) 24:1506-14
Puga, Guilherme M; Meyer, Christian; Mandarino, Lawrence J et al. (2013) Increased plasma availability of L-arginine in the postprandial period decreases the postprandial lipemia in older adults. Nutrition 29:81-8
Puga, Guilherme M; Meyer, Christian; Mandarino, Lawrence J et al. (2012) Postprandial spillover of dietary lipid into plasma is increased with moderate amounts of ingested fat and is inversely related to adiposity in healthy older men. J Nutr 142:1806-11
Zhang, Xiangmin; Højlund, Kurt; Luo, Moulun et al. (2012) Novel tyrosine phosphorylation sites in rat skeletal muscle revealed by phosphopeptide enrichment and HPLC-ESI-MS/MS. J Proteomics 75:4017-26
Puga, Guilherme M; Meyer, Christian; Everman, Sarah et al. (2011) Postprandial lipemia in the elderly involves increased incorporation of ingested fat in plasma free fatty acids and small (Sf 20-400) triglyceride-rich lipoproteins. Am J Physiol Endocrinol Metab 301:E356-61
Xie, Xitao; Yi, Zhengping; Bowen, Benjamin et al. (2010) Characterization of the Human Adipocyte Proteome and Reproducibility of Protein Abundance by One-Dimensional Gel Electrophoresis and HPLC-ESI-MS/MS. J Proteome Res 9:4521-34