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.

Study Overview

• Status: Completed
• Conditions: Obesity; Insulin Resistance
• Intervention / Treatment: Other: Over feeding

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• BMI 25-35 kg/m2
• Healthy adults
• Age 35-65
• Weight stable
• Nondiabetic

Exclusion Criteria:

• Major organ disease such as heart, kidney, liver
• Malignancy
• Inflammatory conditions (eg. lupus, rheumatoid arthritis, Crohn's disease)
• Eating disorder h/o bariatric surgery or liposuction use of blood thinners such as Coumadin (aspirin is ok)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Insulin resistant; 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
Experimental: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subcutaneous adipose cell triglyceride storage capacity/differentiation	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	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ectopic fat	Fat deposited in liver (MRI), visceral (intraabdominal) abdominal (CT) versus subcutaneous abdominal and thigh fat (CT)	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adipose tissue and systemic inflammation: both innate or adaptive immune response	Flow cytometry will be used to quantitate, in both adipose tissue and plasma, populations of dendritic cells, T-cell subpopulations, and macrophages	3 years

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Tracey McLaughlin, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2011
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: March 12, 2013
• First Submitted That Met QC Criteria: March 9, 2014
• First Posted (Estimated): March 12, 2014

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 10, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: obesity; inflammation; macrophage; overfeeding; adipocyte; ectopic fat; intrahepatic fat; triglyceride storage; adipocyte proliferation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: 20281