Interactions between PPAR, embryonic nutrition, and the developmental origins of metabolic dysfunction

University Of Massachusetts Amherst, Amherst MA

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Abstract

PROJECT SUMMARY One of the best characterized pathways implicated in metabolic dysfunction is the activation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which guides cellular processes pertaining to adipogenesis and nutrient utilization. Developmental exposures to PPAR-activating toxicants have been widely associated with low birth weight, and yet, these individuals have increased risk for obesity and diabetes later in life. Pharmacological activation of PPAR signaling is the mode of action for some of the most effective drugs for Type II Diabetes. However, chronic exposures to environmental PPAR activators are associated with increased risk for metabolic syndrome in adulthood. The spatiotemporal mechanisms guiding this shift in metabolic efficiency require extensive characterization. Preliminary data demonstrates that embryonic exposure to perfluorooctanesulfonic acid (PFOS), a PPAR? activator, alters pancreas morphology and embryonic expression of hormones and digestive enzymes crucial for metabolism. The goal of this study is to identify the mechanisms by which toxicant-induced PPAR activation perturbs embryonic nutrition, yet increases susceptibility to metabolic syndrome later in life. The first aim of this study will determine the mechanisms by which PFOS-induced PPAR signaling perturbs embryonic nutrient uptake, distribution and metabolism in the zebrafish embryo?a homologous model for human embryonic nutrition. The second aim of this study will discover windows of susceptibility during which chronic exogenous PPAR activation can influence pancreatic ?-cell resilience and function, and can increase risk for obesity and diabetes. Overall, this project serves to elucidate a relationship between exogenous PPAR activation, embryonic nutrition, and metabolic syndrome later in life. This project directly addresses the goals of NIEHS to: 1) provide a mechanism by which developmental exposures to PPAR- activating compounds directly affects embryonic uptake, distribution, and metabolism, and 2) identify the longitudinal pathologic and biochemical consequences of these same exposures to identify key windows of susceptibility to metabolic dysfunction throughout the lifecourse.