IMPH Research in Obesity

Addressing Health Literacy and Numeracy to Prevent Childhood Obesity 
Biomarkers of Obesity, Prostate Tissue Inflammation, and BPH Progression 
Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer 
Growing Right Onto Wellness (GROW): Changing Early Childhood BMI Trajectories 
Modifiable Risk Factors for Fatal Prostate Cancer: A Prospective Study in Asia 
Molecular and Cellular Basis for the Efficacy of Bariatric Surgery 
O'Brien Center Development: BPH and Obesity 
RYGB Improves Metabolism by Interrupting the Gastric Adipose Tissue Axis

Addressing Health Literacy and Numeracy to Prevent Childhood Obesity

In 2003, Surgeon General Richard Carmona stated that low health literacy was "one of the largest contributors to our nation's epidemic of overweight and obesity." This assertion is supported by recent studies which have found that low health literacy or numeracy is associated with poorer caregiver breastfeeding knowledge, incorrect mixing of infant formula, difficulty understanding food labels and portion sizes, and higher Body Mass Index (BMI) in adults and children. Of particular concern is the impact of the obesity epidemic on our youngest children. Over 26% of preschool children are now overweight (BMIe85%) or obese (BMIe95%) (based on 2007 HHS/CDC Expert Panel definitions). Rates of obesity in preschool children have doubled over the past decade, with the highest increases among low income and minority children-- the same communities most affected by low health literacy. To date, clinical efforts to prevent or treat childhood obesity have had limited efficacy. Efforts need to start early, because children who are overweight by age two are five times as likely to become overweight adolescents, and subsequently at higher risk for obesity-related complications including early-onset Type-2 Diabetes and cardiovascular disease. No published clinical studies have rigorously addressed obesity prevention prior to age 2 with a specific low-literacy and numeracy focus. Addressing caregiver health literacy in early childhood is an innovative strategy to promote healthy nutrition and activity among these families and prevent unhealthy weight gain across the child's life, which would have great public health significance by preventing both child and adult chronic illness. The proposed study is a multi-site randomized, controlled trial to assess the efficacy of a low- literacy/numeracy-oriented intervention designed to promote healthy family lifestyles and to prevent early childhood obesity. The intervention will be delivered through pediatric resident physicians in primary care settings in under-resourced communities. Four academic medical centers will be randomized: Vanderbilt University, the University of Miami, the University of North Carolina at Chapel Hill, and New York University. Two centers will receive the intervention, while the other two centers will receive an active control. At each site, a cohort of 250 English- or Spanish-speaking caregiver-child dyads will be enrolled and followed from the child's 4-6 month well-child visit through the 24-month well-child visit. The intervention will include a low- literacy-oriented toolkit for pediatric residents to use with families and clear health communication training for the pediatric residents. At control sites, pediatric residents will provide "usual care" with respect to lifestyle counseling, but they will also receive an injury-prevention education program to act as an attention control. The primary hypotheses are that the intervention will improve family dietary and physical activity behaviors and that it will reduce the rate of childhood overweight (BMIe85%) at age 24 months. Project Narrative In 2003, Surgeon General Richard Carmona suggested that low health literacy is "one of the largest contributors to our nation's epidemic of overweight and obesity." Over 26% of preschool children are now overweight or obese, and children who are overweight by age 24 months are five times as likely as non- overweight children to become overweight adolescents. The aim of the study is to assess the efficacy of a low- literacy/numeracy-oriented intervention aimed at teaching pediatric resident physicians to promote healthy family lifestyles and prevent overweight among young children (age 0-2) and their families in under-resourced communities. Read more.

Funding Source: NIH/NICHD
PI: Russell Rothman

Biomarkers of Obesity, Prostate Tissue Inflammation, and BPH Progression

The purpose of the study is to investigate the relationship between obesity and BPH.  Obesity generates a state of chronic systemic inflammation known to enhance arthrosclerosis, diabetes, and other inflammatory diseases. Several studies also suggest that obese men are also more likely to develop lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).  However, much of the epidemiologic evidence relies on self-reported BPH outcomes, and there are few, if any, animal models to characterize the obesity-BPH relationship. Thus, our long-term goals are to characterize the relationship between obesity and prostate tissue inflammation and hyperplasia, investigate potential mechanisms by which obesity advances BPH, develop a mouse model of BPH for mechanistic studies, and to conduct a prospective epidemiologic study to investigate the clinical impact of obesity on BPH progression. Read more.

Funding Source: NIH/NIDDK
Pi: Jay Fowke

Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer

Prostate cells respond to estrogens, insulin, and other factors largely regulated in men by adipose mass. Several recent studies report obesity associated with high-grade prostate cancer, progression, and mortality, however the association with low-grade cancer common in the PSA era remains unclear. Challenges include measuring fat deposition patterns, excluding latent cancer from control groups, and controlling for several potential biases associated the effects of obesity on prostate cancer detection. Our study aims to address these challenges and determine the relationship between total adiposity (e.g., BMI, estrogens) and visceral adiposity (e.g., waist circumference, WHR, insulin) across high-grade cancer, low-grade cancer, and prostatic intraepithelial neoplasia (PIN). Preliminary analyses (R21 CA98348, n=304 cancer, 120 PIN, 424 controls) found WHR significantly associated with PIN (WHR>1.03: OR = 4.75 95% Cl (1.71, 13.2), ptrend<0.01, adjusted for PSA, BMI, prostate volume, age race, ORE result, # cores). Also, BMI>35 was associated with high-grade (Gleasons7) cancer (ORadj=3.49 (0.84, 14.4), ptrend = 0.05). Thus, visceral adiposity and the related metabolic syndrome may impact early prostate carcinogenesis, while an estrogen- rich environment associated with greater BMI may accelerate progression to high-grade/clinically relevant disease. Using our established multi-centered rapid-recruitment protocol, we will recruit an additional 1,106 prostate cancer cases (42% Gleason &7), 435 PIN cases, and 1,544 controls without cancer or PIN at prostate biopsy. Data and specimens (questionnaires for diet, physical activity, and other risk factors; body measures for BMI, WHR, sitting height, and % body fat (BIA); blood for DNA and hormone levels) are collected before diagnosis. Genes representing pathways linking total adiposity (e.g., Lep, LepR, CYP19, ER,AR, SHBG) or visceral adiposity (Res, Adip, AdipR1/2, INS, IRS1/2, IGF1, IGFBP3, PPARy2) to PIN or cancer will be investigated using multivariable logistic regression. Also, we will investigate blood markers of adiposity and PIN in an individually matched analysis (total adiposity: leptin, E2/T ratio, SHBG; visceral adiposity: HbA1c, adiponectin, resistin). Obesity is epidemic in the U.S., and prostate cancer is a leading cause of cancer-related death. Ongoing chemoprevention studies target PIN, and our results may identify new obesity-based prevention approaches or improve the prognosis of prostate cancer patients. Read more.

Funding Source: NIH/NCI
PI: Jay Fowke

Growing Right Onto Wellness (GROW): Changing Early Childhood BMI Trajectories

Food preferences and activity habits set in early childhood can profoundly influence lifelong trajectories for Body l\/lass Index (BMI) and health. Specifically, rapid BMI gain in early childhood has been established to affect adulthood mortality and morbidity. Unfortunately, the longer such unhealthy patterns are in place, the more difficult it can be to reverse them. Therefore, healthy lifestyle interventions targeted at children as early as preschool 'have enormous potential to affect lifelong health. Furthermore, nutrition and activity patterns are determined not only at the child level, but within the family and the community. Building on the success of an existing partnership between Vanderbilt Pediatrics and Metro Parks and Recreation in Nashville, TN, we will conduct and evaluate an intervention intended to prevent obesity in preschoolers in an approach that affects multiple levels of risk and is both family-based and community centered. Prior to launching a large randomized controlled trial (RCT), formative research (focus groups and pilot studies) will be conducted to refine the intervention components. In the RCT, 600 parent-preschool children dyads from low income neighborhoods will be randomly assigned to one of two conditions. In the intervention condition, groups of parent-child dyads will participate in an empirically tested, literacy-sensitive, skills building curriculum to improve: 1) caloric intake with appropriate macronutrients, and 2) routine physical activity for both parent and child. The intervention condition will occur in community centers and utilize tools including goal setting, self-monitoring, and problem solving. In the control condition parent-child dyad groups will receive a literacy promotion/school success curriculum. Both conditions will have 90-minute sessions in: 1) an initiation phase (weekly for 3 months); 2) a maintenance phase (biweekly for 6 months); and 3) a sustainability phase (monthly for 27 months). The primary outcome of interest will be early childhood BMI trajectories measured at multiple time points over the three year RCT. Additional measures collected throughout the study from children and parents will include: bioelectrical impedance; waist circumference; actigraphy; 3-day diet recalls; questionnaires; social network data; and saliva to assess a genetic risk score associated with obesity. RELEVANCE: Pediatric obesity prevention must occur in preschool given that 60% of oven/weight preschoolers will go on to become overweight adolescents. By conducting and testing trials in public community centers, exportable interventions could result allowing for a macro-level system change to address this expanding public health crisis. Read more.

Funding Source: NIH/NHLBI 
PI: Shari Barkin

Modifiable Risk Factors for Fatal Prostate Cancer: A Prospective Study in Asia

Our overarching goal is to identify modifiable risk factors for fatal prostate cancer. Prostate cancer remains the second leading cause of cancer-death in the United States (U.S.), but known demographic and genetic risk factors have limited value in delaying progression. Further investigation in U.S. populations is problematic because widespread and selective prostate-specific antigen (PSA) testing is so strongly associated with the stage at diagnosis that any association between a risk factor and PSA testing could easily overwhelm a modest by important etiologic association. To remove this known detection bias, we propose a prospective investigation to determine the association between obesity, tobacco, and alcohol use with fatal prostate cancer using data from the Asian Cohort Consortium (ACC). Asian nations rarely perform PSA tests, and most prostate cancer patients in Asia are diagnosed with advanced or metastatic disease. The ACC is a unique resource that has harmonized data across 15 prospective cohort studies and includes over 450,000 men with approximately 3.5 million person-years follow-up. Prostate cancer is far less common in Asia than the U.S., and a prospective study would only be possible with such a consortium. Using a nested case- control design, each of the 507 recorded prostate cancer deaths to date will be individually matched to 10 controls by age (1 year) and cohort. Multivariable conditional logistic regression will be used to investigate associations between BMI, tobacco, and alcohol use with fatal prostate cancer. This project provides an exceptional opportunity to provide the first systematic prospective investigation of modifiable factors for fatal prostate cancer, while minimizing detection bias from selective PSA testing and subsequent treatment. Our results may form the basis for recommendations to prevent prostate cancer mortality in Asia, and more generally, in populations that are not routinely PSA-tested. Furthermore, results may also form the basis for adjuvant care recommendations among men diagnosed with localized disease by at risk for progression to an advanced stage and for death. Read more.

Funding Source: NIH/NCI 
PI: Jay Fowke

Molecular and Cellular Basis for the Efficacy of Bariatric Surgery

Bariatric surgery is currently the only effective treatment for severe obesity, and the only effective cure for type II diabetes. Research on the mechanism of action of the different bariatric surgical procedures in humans and model systems including pigs, dogs, rats, and mice supports the hypothesis that the beneficial effects result from more than the restrictive or malabsorptive effects of the procedures on food intake. Indeed, data argue that neuroendocrine changes in gut-brain signaling resulting from the Roux-en-Y and gastric sleeve procedures alter satiety, hunger, food preferences, and glucose homeostasis prior to the achievement of significant weight loss. Understanding the cellular and molecular basis of these changes induced by bariatric surgery might lead to the development of pharmaceutical interventions, or improved surgical procedures for the treatment of obesity and diabetes. While several animal models can be used for research on the physiology of bariatric surgery, the mouse provides the best model for studies of cellular and molecular mechanisms because transgenesis can be used to alter individual genes, and to label specific cell types. We show results here demonstrating successful creation of murine bariatric surgery models at Vanderbilt, and the use of the models to identify the first gene that plays an essential role in th efficacy of RYGB for long term maintenance of significant weight loss. The unique hypothesis to be tested is that the efficacy of bariatric surgery results not solely from a collection of changesto Gl signaling, but rather that essential changes in both Gl signaling AND in the plasticity and responsiveness of CNS homeostatic and hedonic circuits act synergistically to restore glucose homeostasis, and create a new weight set point. In this interdisciplinary team grant application, we bring together leading experts in human and murine bariatric surgery, murine pathology, Gl anatomy and function, obesity and diabetes, and quantitative human genetics to jointly study surgical preparations from humans and mice in order to identify the genes and cell types mediating the efficacy of bariatric surgery. Read more.

Funding Source: NIH/NIDDK
Pi: Roger Cone

O'Brien Center Development: BPH and Obesity

This is toward development of a Center to investigate obesity and BPH.  We conduct two epidemiologic investigations to determine if prostate tissue inflammation or LUTS severity is associated with hypothesized pathways linking obesity to BPH, including increased PGE-M (inflammation), F2-isoprostanes (oxidative stress), and adiponectin and C-peptide (insulin activity).

Funding Source: NIH/NIDDK 
IMPH Faculty: Jay Fowke

RYGB Improves Metabolism by Interrupting the Gastric Adipose Tissue Axis

Obesity is a major public health problem; nearly 60% of the US population is considered obese or overweight. More alarming is the increase in prevalence of "super-obesity" (Class III obese) reaching in some localities 7% of the population, as in Tennessee where the PI resides. This condition is associated with severe co- morbidities, such as cardiovascular disease and type 2 diabetes, many of which are attributed to chronic inflammation, oxidative stress and insulin resistance. Roux-en-Y gastric bypass (RYGB) surgery is the most effective and sustainable weight loss procedure. Data of ours and others have shown that many of the metabolic benefits of RYGB occur in the first week postoperatively, prior to significant weight loss. These improvements are preceded by significant reductions in the circulating levels of gastric-derived ghrelin and leptin, occurring as early as 15 minutes after the surgical interruption of stomach during the RYGB procedure. These changes associate with significant reductions in oxidative stress in adipose tissue. The general hypothesis is that RYGB results in interruption of a gastric-adipose tissue axis leading to immediate (within the first week) improvements in oxidative stress and insulin sensitivity. In specific aim 1 we will examine the cellular, tissue-specific and whole-body metabolic alterations 7 days following RYGB. Two cohorts of matched controls will be studied before and 7 days following caloric restriction (to match the post-RYGB diet) without stomach interruption: one with LAGB (laparoscopic adjusted gastric banding) and the other without any surgical procedure. In specific aim 2 we will examine whether ghrelin replacement (restoration of unacylated to acylated ghrelin ratio) in the first week following RYGB reverses improvements in oxidative stress in adipose tissue and in insulin sensitivity. We will utilize three complimentary and comprehensive approaches: (i) In vivo studies to determine insulin sensitivity in liver and skeletal muscle and microdialysis of subcutaneous adipose tissue to assess tissue-specific oxidative stress, cytokine production and lipolysis. We will correlate metabolic improvements to intra-hepatic triglyceride content using magnetic resonance spectroscopy (MRS), and visceral adipose tissue mass using MRI and dual-energy x-ray absorptiometry (DXA). (ii) Ex vivo studies will assess mechanistic aspects of stomach-derived peptides on markers of oxidative stress and inflammation in adipose tissue explants. (iii) In vitro studies will examine changes in: (a) cellular factors of ROS production and pro- and anti-oxidative stress enzymes in adipose tissue biopsies (b) adipose tissue macrophage content via flow cytometry, RT-qPCR and immunohistochemistry (c) cellular factors involved in insulin signaling in adipose tissue and skeletal muscle. The information derived could lead to the combination of less invasive surgical procedures with pharmacologic manipulation of the levels of acylated ghrelin and/or leptin for the treatment of morbid obesity. Read more.

Funding Source: NIH/NIDDK
PI: Naji Abumrad