Insulin resistance (IR) is a major contributor to obesity-related morbidities such as diabetes and cardiovascular disease. While obesity is associated with IR, the biological basis for this association is unclear, and not all obese individuals are IR. The once-popular portal hypothesis, which states that lipolysis from VAT in particular accounts for IR, has been questioned because VAT contributes only 15% of the total systemic free fatty acid (FFA) flux. Other proposed mechanisms linking obesity to IR include inflammation, adiponectin, and ectopic fat. It is unclear whether VAT mass is more closely linked to IR than is subcutaneous adipose tissue (SAT) mass. Furthermore, evidence linking differential biological activity to IR in VAT or SAT is indirect, largely derived from studies comparing lean to obese or VAT to SAT without evaluation of IR. Thus, the purpose of this study is to investigate the biological mechanisms by which SAT and/or VAT contribute to IR. Specifically, we will explore two related hypotheses- that impaired adipocyte differentiation in SAT is related to IR, ectopic fat deposition and expansion of VAT depot, and that inflammation in VAT is associated with IR. Utilizing adipose cell size/distribution obtained by Beckman Coulter Multisizer, gene expression via quantitative PCR, in-vivo quantification of IR via a modified insulin suppression test, and imaging of intramyocellular, intraabdominal and intrahepatic fat, our specific aims are to: 1) Confirm that impairment of adipocyte differentiation in SAT is associated with IR by comparing cell size characteristics and differentiation markers in IR and IS subjects undergoing elective surgery;2) Test the hypothesis that the same relationship will not be seen in VAT;3) Demonstrate that VAT mass is expanded in the presence of impaired differentiation of adipocytes in SAT;4) Demonstrate that intramuscular fat is related to both IR and impaired differentiation of adipocytes in SAT using cell size characteristics and differentiation markers;5) Demonstrate that increased inflammation in omental fat is associated with IR independent of obesity using inflammation markers (gene and protein). Supportive data for #1,3,4 above will be derived from pioglitazone vs placebo administration to 20-23 IR individuals for 16 weeks, with hypothesized improvement in adipose cell differentiation/fat storage and associated reduction in ectopic and visceral fat with improved insulin sensitivity.

Public Health Relevance

The prevalence of obesity continues to rise in the United States and worldwide, bringing with it associated complications of type 2 diabetes and cardiovascular disease. Insulin resistance (IR) is associated with increasing body mass index (1), and is likely to account for the majority of these complications (2). Not all obese individuals are IR, however (3,4), and there exist sufficient data to justify investigating biological characteristics of adipose tissue that might explain the development of obesity- associated IR in select individuals: 1) weight gain/loss and drugs targeting fat cells (thiazolidinediones) have the ability to alter insulin sensitivity (5,6);2) lipodystrophy models in humans and animals are associated with altered deposition of fat and IR (7-9);3) fat deposition in the abdominal cavity, liver, and skeletal muscle is associated with IR (10);4) inflammatory activity in adipose tissue is higher in obese vs lean individuals (11), suggesting a possible link with IR;5) adipose tissue produces hormones such as adiponectin (12), that may protect individuals from IR. By comparing biological properties of subcutaneous and visceral adipose tissue from obese individuals who are IR vs insulin sensitive, we will explore the hypothesis that impaired differentiation/maturation of adipose cells in subcutaneous fat, and inflammation in visceral fat contributes to IR in the setting of human obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080436-03
Application #
8091283
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Haft, Carol R
Project Start
2009-07-05
Project End
2013-03-30
Budget Start
2011-07-01
Budget End
2013-03-30
Support Year
3
Fiscal Year
2011
Total Cost
$376,154
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Allister-Price, Candice; Craig, Colleen M; Spielman, Dan et al. (2018) Metabolic markers, regional adiposity, and adipose cell size: relationship to insulin resistance in African-American as compared with Caucasian women. Int J Obes (Lond) :
Allister, Candice A; Liu, Li-fen; Lamendola, Cindy A et al. (2015) In vivo 2H2O administration reveals impaired triglyceride storage in adipose tissue of insulin-resistant humans. J Lipid Res 56:435-9
McLaughlin, T; Lamendola, C; Coghlan, N et al. (2014) Subcutaneous adipose cell size and distribution: relationship to insulin resistance and body fat. Obesity (Silver Spring) 22:673-80
McLaughlin, Tracey; Liu, Li-Fen; Lamendola, Cindy et al. (2014) T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol 34:2637-43
McLaughlin, Tracey; Yee, Gail; Glassford, Alec et al. (2011) Use of a two-stage insulin infusion study to assess the relationship between insulin suppression of lipolysis and insulin-mediated glucose uptake in overweight/obese, nondiabetic women. Metabolism 60:1741-7
Winer, Daniel A; Winer, Shawn; Shen, Lei et al. (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17:610-7
McLaughlin, Tracey M; Liu, T; Yee, Gail et al. (2010) Pioglitazone increases the proportion of small cells in human abdominal subcutaneous adipose tissue. Obesity (Silver Spring) 18:926-31
Daigle Jr, Bernie J; Deng, Alicia; McLaughlin, Tracey et al. (2010) Using pre-existing microarray datasets to increase experimental power: application to insulin resistance. PLoS Comput Biol 6:e1000718
McLaughlin, T; Deng, A; Yee, G et al. (2010) Inflammation in subcutaneous adipose tissue: relationship to adipose cell size. Diabetologia 53:369-77
Liu, Alice; Sonmez, Alper; Yee, Gail et al. (2010) Differential adipogenic and inflammatory properties of small adipocytes in Zucker Obese and Lean rats. Diab Vasc Dis Res 7:311-8

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