Obesity and metabolic disease pilot projects
- Environmental determinants of physical activity and obesity
- Oxidative stress in the obese/diabetic heart
- Genetic and early life origins of obesity, metabolic and cancer-related risk factors among Filipinos
Uric acid is the end product of purine metabolism in humans. Elevated serum uric acid (SUA) or hyperuricemia increases the risk for diseases such as gout, hypertension, chronic kidney disease and cardiovascular disease. Hyperuricemia in children is an indicator of adult onset hypertension and cardiovascular risk. Several studies have been conducted to identify genetic loci that may affect SUA. However, none of these studies have been conducted in children or investigated the effects of gene by environment interaction on SUA. Given the important role of nutrients in SUA regulation, we propose to identify and characterize putative functional variants that interact with nutrients to influence SUA levels in children. To achieve this goal we have the following specific aims: i) Identify variation in transcribed regions of genes that are associated with SUA levels; and 2) Determine the effect of interaction of the functional variants with nutrients on SUA levels. This study will reveal functional variants that interact with nutrients to influence serum uric acid in children and provide novel targets for treating these painful diseases by dietary interventions early in life.
The Role of TOA in adiponectin and insulin signaling
Principal Investigator: Terry P. Combs, PhD, Assistant Professor of Nutrition, School of Medicine and Gillings School of Public Health
Adiponectin is a hormone noted for its insulin-sensitizing, anti-atherogenic, anti-inflammatory and cancer resistant properties. Thus, environmental factors that lower circulating levels adiponectin contribute to the greatest public health problems in the US, type II diabetes, cardiovascular disease and cancer. Environmental factors that reduce circulating adiponectin include elements of the built environment that cause obesity, cigarette smoke, chemicals used to produce food and water containers and endotoxin on air particles. How does the reduction of circulating adiponectin cause disease? Our current model suggests that low adiponectin impairs the insulin signaling pathway giving rise to insulinemia and glycemia. We will examine the function of a new protein called TOA (target of adiponectin) in the adiponectin signaling pathway. We will specifically determine whether adiponectin and insulin lead to the phosphorylation of TOA (Aim 1), identify the intracellular location of TOA (Aim 2) and determine whether TOA controls glucose production by a glucose sensing mechanism (Aim 3). Investigating the signaling pathway that mediates the effects of adiponectin will lead to a better understanding of the interactions between environmental factors and the pathogenesis of human disease.
The obesity epidemic is presenting a major public health challenge. Identifying new strategies for regulating energy storage is therefore an important goal. The proposed research will investigate the interaction between two environmental factors that influence energy storage: the diet and intestinal bacteria. The presence of bacteria in the gut leads to an increase in body fat due to microbial suppression of intestinal expression of Fasting-induced adipose factor (Fiaf). The mechanisms underlying bacterial suppression of Fiaf are undefined, and represent potential therapeutic targets for manipulating human energy storage. We have used the zebrafish model to show that the host-bacteria interactions controlling Fiaf expression are sensitive to dietary protein levels. Moreover, we have identified a signaling mechanism used by bacteria to control Fiaf expression. The objective of this proposal is to determine if dietary protein levels influence the composition and activity of the intestinal bacterial community and thereby regulate host metabolism. The proposed research will address the central hypothesis that dietary protein potentiates the bacteria-mediated suppression of Fiaf production by the intestinal epithelium.
Obesity-associated proinflammatory state and insulin resistance play an important role in the development of metabolic syndrome. STAT3 is a transcription factor that mediates the signaling of proinflammatory cytokines, induces cell cycle progression, and prevents apoptosis. This proposal tests the hypothesis that STAT3 in adipose tissue regulates the expression of proinflammatory genes and STAT3 deficiency in this tissue results in the inhibition of proinflammatory state, thus preventing insulin resistance. This hypothesis is based on our preliminary data showing that the ASKO mice are obese, but not diabetic when fed a low-fat diet. The specific aims are to: 1) determine the inflammatory status of low-fat diet fed ASKO mice; 2) determine whether a high-fat diet induces a proinflammatory state and insulin resistance in ASKO mice; and 3) determine what genes are affected in the adipose tissues of high-fat diet fed ASKO mice. This study will generate important pilot data for a future R01 proposal. It will help to understand the interaction between obesogenic environmental factors and developmental determinants of obesity and metabolic syndrome and to inform studies of new therapeutic approaches.
In mice commensal gut microflora promote suppress intestinal fasting induced adipocyte factor (Fiaf) mRNA and promote adiposity. Gut microflora also induce cytokines implicated in obesity associated insulin resistance. We will use existing colon biopsy RNA from a human population characterized for BMI, waist: hip ratio, plasma insulin and glycated hemoglobin (Hb1Ac). We will test the hypothesis that in humans, low expression of colonic Fiaf, and elevated expression of pro-inflammatory cytokines predict obesity and early signs of insulin resistance. We also hypothesize that obesity and altered Fiaf or cytokines reflect increased load of total or specific colonic commensal bacteria. Aim 1 : real time PCR will quantify expression of Fiaf, cytokines and a panel of 16S rRNAs specific to common bacteria in 580 human colon RNA samples. Aim 2: logistic regression will test for associations between Fiaf, cytokine expression levels, or bacterial RNAs and BMI, waist to hip ratio, plasma insulin or Hb1Ac levels. Overall, we aim to define new biomarkers for bacterial colonization or responses to colonization in gut, and establish if these predict obesity or insulin resistance.
Background. With minimal research, particularly longitudinal analysis, there is an increasing call for population-wide environmental/policy interventions to increase physical activity.
Specific Aims. We will link contemporaneous geographic locations of respondents with physical environment variables and data from the Coronary Artery Risk Development in Young Adults Study [CARDIA], a longitudinal study of 5,115 black and white young adults aged 18-30 years at baseline. The specific aim of the pilot is to develop and validate new physical environment measures from existing databases linked to respondents= geographic locations. Future aims include estimating the dynamic effects of patterns and changes in environment variables on activity.
Methods. We will geocode street addresses for respondents from the CARDIA dataset and build an extensive GIS database of activity-related environmental factors (e.g., park and recreation facilities, transport options, accessibility variables, crime, climate, and community design) using a range of federal, commercial, and public databases. We will develop complex longitudinal and spatial analytical models to explore relationships between environmental factors and activity, adjusting for self-selectivity of residential location choice. This will be the first longitudinal study of its kind.
An obesogenic environment exists in the US in which obesity and diabetes flourish. Obesity and subsequent diabetes leads to a concomitant increase in heart disease. Hearts from obese and diabetic rodents exhibit deranged fatty acid (FA) metabolism, with increased rates of mitochondrial and peroxisomal FA oxidation and accumulation of triacylglycerol (TAG). The presence of hydrogen peroxide, elevated catalase, and a diminished ratio of reduced gluatathione (GSH) to oxidized glutathione (GSSG) indicate the presence of oxidative stress. Hyperlipidemia is associated with increased tissue concentrations of lipid peroxides (TBARS); therefore, excess myocardial TAG may contribute to elevated levels of TBARS in the obese/diabetic heart. We hypothesize that altered FA metabolism in the obese/diabetic heart induces oxidative damage which results in the observed heart disease. Mice will be fed either a high fat, high sucrose diet to induce obesity/diabetes or a control diet. We will evaluate the following: a) extent of myocardial TAG accumulation, b) up-regulation of peroxisomal oxidation, c) oxidative state of the heart (GSH/GSSG ratio), d) extent of lipid peroxidation (TBARS/MDA; Nutrient Assessment Facility Core), e) extent of DNA damage (8-OH-dG and M1G; Biomarkers Facility Core), and f) up-regulation of base excision repair (BER) genes. Results from these studies will provide preliminary data for an RO1 proposal investigating obesity/diabetes-induced heart disease.
The proposed research focuses on the identification of early life exposures, genetic main effects, and gene-environment interactions contributing to the development of obesity and other components of the metabolic syndrome among Filipino young adults. We use detailed, prospectively collected data from The Cebu Longitudinal Health and Nutrition Survey, an ongoing sociodemographic study to which we will add blood collection for analysis of DNA and plasma biomarkers of CVD risk. The sample includes about 2000 individuals born in 1983-84, and their mothers. This rich data set allows us to examine interactions of prenatal and early life nutritional exposures, selected genotypes, and diet and physical activity as determinants of outcomes. We also include genetic and phenotypic data on the mothers of young adults. Our ultimate research goal is to model a wide range of obesity-related phenotypes reflected in weight gain trajectories from the prenatal period to adulthood, subcutaneous fat patterning, other markers of central obesity, and a suite of biomarkers of CVD risk (insulin resistance using HOMA, fasting glucose and insulin, leptin, C-reactive protein and other markers of inflammation, and serum lipids).