Regional Fat Depots and Insulin Resistance

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, the investigators 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 CT scans of
abdomen/thigh, 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).

Inclusion Criteria:

- No major organ disease

- Fasting blood glucose < 126 mg/dL

- BMI 25-35 kg/m2

- Nonpregnant/nonlactating

Exclusion Criteria:

- pregnancy/lactation

- major organ disease

- drugs that influence insulin resistance

- unstable body weight or active weight loss program

- outside BMI range or age range

- diabetic by fasting glucose criteria 126 mg/dL or higher