Genetic and environmental contributions to obesity pathogenesis - PROJECT SUMMARY ABSTRACT The genetic basis of obesity is well documented through classical twin studies and modern sequencing methods that generate genome-wide polygenic risk scores. The strong influences of socioeconomic, environmental, and health-behavior risk factors for obesity have also been identified. However, neither genetic nor environmental factors alone can explain the rapid rise in obesity prevalence over the past forty years. It is likely that the underlying biological drivers of the obesity epidemic lie at the intersection of genetics and the modern environment. The overall goals of the proposed research are to fill gaps in our understanding of the neurobiological underpinnings of genetic risk factors for common obesity, and to probe mechanisms whereby genetic factors may magnify the risk of environmental exposures through effects on the brain. Specifically, rodent models indicate that dietary exposures cause cellular inflammation – known as gliosis – in the mediobasal hypothalamus, which contains the arcuate nucleus, leading to dysfunction of local neurons that regulate body weight, increases in adiposity, and obesity. The cumulative literature from translational studies supports a role for hypothalamic inflammation and gliosis in the pathogenesis of obesity in humans. However, genetic susceptibilities that modify the extent to which obesogenic diets stimulate hypothalamic inflammation and gliosis remain largely uninvestigated. It is also possible that potent environmental stimuli promote hypothalamic gliosis regardless of genetic makeup which could have broad implications for population health. The proposed research therefore uses epidemiologic and twin study approaches to 1) test genetic risk factors for hypothalamic gliosis and 2) test environmental risk factors for obesity and hypothalamic gliosis and determine, through twin study methods, if environmental factors act independently of genetic background to promote obesity and/or hypothalamic gliosis. The proposed studies will utilize genetically informative samples from the Framingham Heart Study, the Adolescent Brain Cognitive Development Study, a brain tissue repository, and the Washington State Twin Registry. Hypothalamic gliosis will be measured both in vivo using magnetic resonance imaging and post-mortem using histopathology performed on hypothalamic tissue. Genotype-phenotype association study designs include both candidate gene and genome-wide approaches. Twin studies are used to disambiguate inherited, environmental, and health behavior risk factors for obesity and hypothalamic gliosis. In sum, the proposed research could significantly impact the field by uncovering molecular and neurobiological pathways involved in obesity pathogenesis, advancing our understanding of the influence of genetic factors on hypothalamic inflammation and gliosis, and opening avenues for novel mechanistic studies or precision health interventions.
