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Targeting the Keap1/Nrf2 pathway in adipose tissue for obesity prevention and treatment (ADIPONRF2)
Start date: May 1, 2013, End date: Apr 30, 2016 PROJECT  FINISHED 

This research addresses the question of how the manipulation of Keap1/Nrf2 signaling in adipose tissue affects the development of obesity and metabolic syndrome. Nrf2 is a central orchestrator of a battery of antioxidant and cytoprotective genes in response to oxidative or electrophilic stress and there is growing evidence that it cross-talks with other pathways. Our previous works showed that the whole body deletion of Nrf2 protected, at least partially, mice from high-fat diet (HFD)-induced obesity and insulin resistance and led to impaired adipogenesis. Another study has shown that mice treated with an Nrf2 activator, the triterpenoid CDDO-Im, were also protected from HFD-induced obesity. However, little is known about the exact mechanisms involved and which tissue is the main contributor to the resulting phenotype. Taking into account that there is in vitro evidence that Nrf2 is implicated in adipogenesis by crosstalking with transcription factors central to the adipocyte differentiation (PPARgamma, C/EBP beta), the main focus of this research will be to develop a murine model with conditional deletion of Nrf2 (loss of Nrf2 function) or Keap1 (gain of Nrf2 function) in adipose tissue using the Cre-recombinase-loxP system. Using both these models we will study how genetic manipulation of Nrf2 specifically in adipose tissue affects the development of HFD-induced obesity, the oxygen and energy consumption, the insulin resistance and the expression of genes involved in adipogenesis and lipid metabolism in adipose and other tissues in the different genotypes. Experiments using primary adipocyte cultures will give a mechanistic insight into adipogenesis and insulin signaling. This work will advance the field of obesity by actually being the first work that scrutinously characterize Nrf2 as a novel target for obesity prevention and treatment and possibly pave the way for relevant future clinical trials using Keap1/Nrf2 pathway modifying agents.
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