Obesity is a major public health problem due to the increase in obesity-related chronic diseases such as type 2 diabetes. The development of obesity-related insulin resistance and type 2 diabetes can be linked to dysregulation of the ability of adipose tissue to adequately store energy in the form of triglycerides, leading to ectopc lipid accumulation in non-adipose tissues. The nuclear hormone receptor peroxisome proliferation-activated receptor gamma (PPAR?) in adipocytes is a key factor in integrating lipid metabolism with glucose homeostasis and insulin sensitivity. Activation of PPAR? by the thiazolidinedione (TZD) class of anti-diabetic drugs is associated with expansion of the adipose tissue and enhanced ability of the adipose tissue to store dietary lipids. These drugs alter PPAR? activity and PPAR? protein levels, an indication that understanding the link between PPAR? activity and PPAR? protein stability may offer new insights into how obesity contributes to NIDDM. PPAR? stability in adipocytes is regulated by enzymes of the ubiquitin proteasome pathway, a highly selective signaling pathway that targets proteins to the proteasome by tagging the protein with multiple ubiquitin polypeptides. Using siRNA-based screening, we identified a ubiquitin ligase, Siah2 that regulates PPAR? protein levels and PPAR? activity in adipocytes. Our preliminary studies using a Siah2KO mouse model show Siah2 regulates PPAR? protein levels and inflammation in adipose tissue and that eliminating Siah2 prevents obesity-related insulin resistance. We hypothesize that Siah2-dependent regulation of PPAR? activity links obesity with adipose tissue inflammation and insulin resistance. Our goal is to provide mechanistic insight into the role of Siah2 in controlling the relationship between PPAR? protein levels, insulin sensitivity and inflammation in adipose tissue.
In Specific Aim 1, we will test the hypothesis that Siah2-dependent modification of PPAR? limits PPAR? activity by increasing ligand-dependent proteasomal degradation of PPAR?.
Specific aim 2 will assess the effect of Siah2 on adipose tissue inflammation.
In specific aim 3, we will test the hypothesis that Siah2 in adipocytes regulates systemic insulin sensitivity via regulation of PPAR? activity and lipid partitioning between adipose and non-adipose tissue. Together, these studies will provide new insight into the relationship between PPAR? activity and the role of adipose tissue in regulating insulin sensitivity and will advance our goal of determining if the ubiquitin-proteasome system represents a novel therapeutic target in the treatment of obesity-related insulin resistance and type 2 diabetes.

Public Health Relevance

We learned that Siah2, an enzyme that belongs to a group of proteins called the ubiquitin- proteasome system, plays a role in determining the relationship between obesity and developing a resistance to insulin's action. We are interested in understanding how Siah2 in fat cells is determining sensitivity to insulin. These studies are relevant to understanding the relationship between adipocyte biology and obesity-related disorders such as metabolic syndrome and type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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Lsu Pennington Biomedical Research Center
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Baton Rouge
United States
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Kilroy, Gail; Dietrich, Marilyn; Wu, Xiying et al. (2018) Isolation of Murine Adipose-Derived Stromal/Stem Cells for Adipogenic Differentiation or Flow Cytometry-Based Analysis. Methods Mol Biol 1773:137-146
Kilroy, Gail; Burk, David H; Floyd, Z Elizabeth (2016) Siah2 Protein Mediates Early Events in Commitment to an Adipogenic Pathway. J Biol Chem 291:27289-27297
Li, Jing Jing; Wang, Ruishan; Lama, Rati et al. (2016) Ubiquitin Ligase NEDD4 Regulates PPAR? Stability and Adipocyte Differentiation in 3T3-L1 Cells. Sci Rep 6:38550
Huang, Jiawen; Cardamone, M Dafne; Johnson, Holly E et al. (2015) Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation. J Biol Chem 290:19044-54
Kilroy, Gail; Carter, Lauren E; Newman, Susan et al. (2015) The ubiquitin ligase Siah2 regulates obesity-induced adipose tissue inflammation. Obesity (Silver Spring) 23:2223-32