Adipose Tissue Response to Overfeeding in Insulin Resistance-Prone vs. Insulin Sensitive Humans

Obesity has become an epidemic worldwide. Data from our laboratory and others demonstrate
that most of the excess morbidity from obesity is related to insulin resistance (IR). While
total adiposity correlates with insulin resistance, not all obese individuals are IR. When
obese IR individuals lose weight in response to caloric restriction, even moderate loss of
body fat results in improved insulin sensitivity (IS). With massive weight loss, either
dietary or surgical, even the most IR individuals can completely reverse their insulin
resistance. But why is one individual IR at a BMI of 26 and another IS at a BMI of 35? There
must be differences in the manner in which adipose cells/tissue respond to caloric excess
and weight gain. One potentially unifying hypothesis with regard to obesity-associated
insulin resistance is that those individuals who fail to respond to caloric excess/obesity
with adequate adipocyte differentiation and expanded subcutaneous fat storage capacity
develop increased circulating FFAs, ectopic fat deposition, stress on adipocytes, triggering
localized and systemic inflammation and ultimately insulin resistance in skeletal muscle.

Clearly, the best way to examine the human response to obesity is to challenge overweight
individuals with the need to store excess triglyceride in adipose tissue. Specific aims are:

1. Test the hypothesis that impaired adipogenesis and fat storage capacity are associated
with insulin resistance by comparing 1) cell size distribution; 2) gene markers of
adipose cell differentiation; 3) differentiation of isolated preadipocytes in IR-prone
vs IS individuals subjected to caloric excess.

2. Determine if circulating (daylong FFA, two-stage Insulin Suppression Test) and ectopic
fat (MRI liver, CT abdomen) are worsened to a greater degree in IR-prone vs IS
individuals subjected to caloric excess.

3. Determine whether differences in inflammation and/or innate or adaptive immune response
are associated with insulin resistance by comparing differences in resident dendritic
cells, macrophages and their activation profiles, changes in T-cell subpopulations, and
other inflammatory mediators in IR-prone vs IS individuals who are subjected to caloric
excess via overfeeding.

4. Exploratory: Evaluate IR-prone vs IS individuals for evidence of hypoxia and
insufficient angiogenic response in response to caloric excess.