1. Jerrold J. Heindel PhD Acting Chief Cellular Organ and Systems Pathobiology Branch National Institute of Environmental Health Sciences National Institutes of Health/DHHS heindelj@niehs.nih.goheindelj@niehs.nih.gov Obesity/Diabetes/Metabolic Syndrome: Proposed Program Development

2. PA: Role of Environmental Chemical Exposures in The Development of Obesity, Diabetes and Metabolic Syndrome –R01 and R21 (Multiple mechanisms and multiple years to stimulate this developing area) Goals –To provide data to prove/disprove hypothesis that environmental chemical exposures during development can lead to weight gain, altered glucose/insulin sensitivity and altered lipid metabolism indicative of obesity, type 2 diabetes and metabolic syndrome in the human population. –To provide data showing HOW environmental exposures can lead to these diseases/dysfunctions. –To Develop biomarkers of exposures that lead to these diseases/dysfunctions that can be used in intervention studies. –To reduce the incidence of obesity/type 2 diabetes and metabolic syndrome (disease prevention).

3. Research Initiative R21 Program To identify new environmental chemicals that have the capacity to alter adipose tissue metabolism, numbers of adipocytes, glucose tolerance/insulin resistance, and or lipid metabolism at the cellular and molecular level. To examine environmental chemicals, shown to increase weight gain, in order to determine if they also affect glucose tolerance/insulin sensitivity and lipid metabolism. To develop biomarkers of exposure in animal models or human studies that would indicate increased susceptibility to obesity, type 2 diabetes and/or metabolic syndrome. To develop and test high-throughput screens to detect chemicals that alter pathways that lead to weight gain, altered metabolism, alter glucose tolerance/insulin sensitivity or lipid metabolism indicating the potential for obesity, type 2 diabetes and/or metabolic syndrome.

4. To understand the site(s) and mechanisms(s) whereby environmental chemicals can lead to altered adipose tissue metabolism, numbers of adipocytes, glucose tolerance/insulin resistance, and or lipid metabolism at the cellular and molecular level. To develop and utilize high-throughput screens to detect chemicals that alter pathways that lead to weight gain, altered metabolism, alter glucose tolerance/insulin sensitivity or lipid metabolism indicating the potential for obesity, type 2 diabetes and/or metabolic syndrome. To understand the interaction of genetic background, nutrition, stress, drugs, infections, alterations in the circadian system and alterations in the immune system with environmental exposures during development that would lead to obesity, type 2 diabetes and/or metabolic syndrome later in life. To develop biomarkers of exposure and predisease that would indicate increased susceptibility to obesity, type 2 diabetes and/or metabolic syndrome. Research Initiative : R01 Program

5. To examine the role of environmental chemical exposures in the phenomenon of metabolic adaptation that leads to the return of fat after dieting Multi PI applications (one with documented expertise in toxicology and environmental health sciences and one with expertise in the basic biology/endocrinology of Obesity, Diabetes or Metabolic Syndrome) are also encouraged. Dose responses should be assessed, internal levels of the environmental agent should be measured and sex differences should examined. Note: weight gain or glucose tolerance not sufficient endpoints. Research Initiative : R01 Program II

6. What are the Public Health Implications of This Research What are the Public Health Implications of This Research? Hypothesis changes focus: Obesity, type 2 diabetes, metabolic syndrome are set (programmed) during development…perhaps in utero. Changes focus from genetics to gene-environment interactions. Changes the focus to prevention. –Focus on pregnancy, early childhood and puberty as sensitive periods –Reduced exposures to environmental agents during development

7. THE END… or just the beginning?