Diet and Metabolic Inflammation

Obesity is a risk factor for several common cancers, including those of the breast, colon, liver, and pancreas. Proposed molecular links between obesity and these types of cancer include systemic inflammation, hyperinsulinemia, and changes in the serum concentrations of sex steroid hormones and adipokines. All of these are strongly linked to low-grade chronic inflammatory processes in expanded adipose tissue. The objective of this proposal is to test the hypothesis that adipose tissue inflammation can be reduced by the foods we eat.

Overweight or obese individuals with evidence of insulin resistance will be enrolled, until 16 have completed all study procedures. Enrolled subjects will be randomized to follow one of two healthy diets for 12 weeks to determine how each diet affects inflammation in the body and sugar and insulin levels in the blood. We will address the following specific aims: Primary specific aim: To investigate whether the consumption of either diet reduces the metabolic activation of adipose tissue macrophages (ATM) as assessed by quantifying the ATM cell surface expression (relative mean fluorescence intensity, rMFI) of the metabolic activation markers, CD36 and ABCA1. Secondary specific aim 1: To compare how each of the study diets affects endpoints downstream of metabolic activation of ATM, specifically (a) adipose tissue expression of the key pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukins (IL)-1 beta and 6; (b) adipose tissue expression of the key anti-inflammatory adipokine, adiponectin; (c) systemic insulin sensitivity, as assessed by the Matsuda-DeFronzo Insulin Sensitivity Index (ISI), based on a 3-hour frequently sampled oral glucose tolerance test (FS-OGTT); and oral glucose tolerance, as assessed by measuring the total area-under-the-curve glucose in the FS-OGTT. Secondary specific aim 2: To compare the impact of each of the study diets on low-grade chronic systemic inflammation, as assessed by measuring the concentrations of high sensitivity C-reactive protein (hsCRP), IL-6, and total adiponectin in fasting plasma. Secondary specific aim 3: To assess dietary adherence in the two dietary intervention groups. Dietary adherence will be measured by a dietary adherence score (separately for each diet), based on repeated 4-day diet records completed by all participants in the study. Because all of our study endpoints are thought to be linked to the gut microbiota, and because the effects of diet may be mediated through changes in the gut microbiota, we will also collect stool samples from all participants before and after completing the study.

Change in adipose tissue macrophage cell surface expression of metabolic activation marker CD36 as measured by relative mean fluorescence intensity

As measured by relative mean fluorescence intensity (rMFI) on abdominal subcutaneous adipose tissue macrophages

Change in adipose tissue macrophage cell surface expression of metabolic activation marker ABCA1 as measured by relative mean fluorescence intensity (rMFI)

As measured by relative mean fluorescence intensity (rMFI) on abdominal subcutaneous adipose tissue macrophages

Change in adipose tissue expression of the key pro-inflammatory cytokine, tumor necrosis factor α (TNFα) assessed by qPCR

Change in adipose tissue expression of the key pro-inflammatory cytokine, interleukin-6 (IL-6) assessed by qPCR

Change in adipose tissue expression of the key pro-inflammatory cytokine, interleukin-1 beta (IL-1beta) assessed by qPCR

Change in adipose tissue expression of the key anti-inflammatory adipokine, adiponectin assessed by qPCR

Assessed by the Matsuda-DeFronzo Insulin Sensitivity Index (ISI) based on a 3-hour frequently sampled oral glucose tolerance test (FS-OGTT)

Change in oral glucose tolerance assessed by measuring total area under the curve glucose in the FS-OGTT

Inclusion Criteria: Body Mass Index (BMI) ≥ 28 kg/m2 Homeostasis model assessment insulin resistance (HOMA-IR) index > 2.0 Body weight within 10% of weight 3 months before starting the study Able to come to the FHCRC Prevention Center for one 1-hour pre-study visit and two clinic visits of ~4.5 hours duration each Able and willing to attend bi-weekly dietary group counseling sessions at FHCRC during the 12-week intervention period Willingness and ability to follow the dietary regimen Able to complete repeated 3-day food records before and during the dietary intervention. Willingness to maintain usual lifestyle habits (other than diet) throughout the study (e.g., physical activity habits) Ability to understand, speak, and write in English Ability to provide informed written consent Exclusion Criteria: Any previous or current use of antidiabetic medications or insulin Presence or history of major chronic inflammatory or autoimmune disease (e.g., lupus, rheumatoid arthritis, Hashimoto's thyroiditis, inflammatory bowel disease, celiac disease, multiple sclerosis), malabsorption syndromes, or diseases of the liver, thyroid, or kidneys (stage IV or later chronic kidney disease) Food allergies or intolerances against major study foods Intake of drugs likely to interfere with study endpoints, including corticosteroids and anabolic steroids, hormone replacement therapy, NSAIDS (more than 3 times per week and/ or more than 600 mg per day), warfarin (within 3 months of starting the study), antibiotics or probiotics (within 2 weeks of starting the study) Presence or recent history of anemia (within 3 months of starting the study) Participation in another study that includes an intervention of any kind or a blood draw >300 mL over 3 months Alcohol intake > 2 drinks per day Use of tobacco products, eCigarettes, or recreational drugs on more than 2 days per month Current or recent (within 12 months of starting the study) pregnancy or breastfeeding