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:
- 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.
- 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.
- 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.
- Exploratory: Evaluate IR-prone vs IS individuals for evidence of hypoxia and insufficient angiogenic response in response to caloric excess.
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||Adipose Tissue Response to Overfeeding in Insulin Resistance-Prone vs. Insulin Sensitive Humans|
- Subcutaneous adipose cell triglyceride storage capacity/differentiation [ Time Frame: 3 years ] [ Designated as safety issue: No ]this will be quantified by measuring: 1) adipose 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; in vivo triglyceride synthesis using stable isotope methods
- Ectopic fat [ Time Frame: 3 years ] [ Designated as safety issue: No ]Fat deposited in liver (MRI), visceral (intraabdominal) abdominal (CT) versus subcutaneous abdominal and thigh fat (CT)
- Adipose tissue and systemic inflammation: both innate or adaptive immune response [ Time Frame: 3 years ] [ Designated as safety issue: No ]Flow cytometry will be used to quantitate, in both adipose tissue and plasma, populations of dendritic cells, T-cell subpopulations, and macrophages
|Study Start Date:||September 2011|
|Estimated Study Completion Date:||December 2016|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
Experimental: Insulin resistant and insulin sensitive
Both groups will be given the same intervention and then outcomes compared between groups
Other: Over feeding
Study participants will be given low saturated fat snacks, an additional 750-1000 calories to gain 6-8 lbs over 4 weeks
Please refer to this study by its ClinicalTrials.gov identifier: NCT02084641
|Contact: Colleen Craig, MD||650-736-2056|
|Contact: Dalia Perelman, RD||650-723-6713|
|United States, California|
|Stanford, California, United States, 94305|
|Contact: Craig, MD 650-736-2056|
|Contact: Lamendola, NP 650-736-2056|
|Principal Investigator:||Tracey McLaughlin, MD||Stanford University|