Maternal Obesity, AMPK and Development of Fetal and Neonatal Gut

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DESCRIPTION (provided by applicant): Maternal Obesity, AMPK and Development of Fetal and Neonatal Gut Meijun Zhu, Developmental Biology Group, Department of Animal Science, University of Wyoming, Laramie, WY 82071 ABSTRACT RATIONAL: Obesity, including obesity of pregnant woman, is increasing rapidly in recent decades. Meanwhile, the incidence of gut related diseases are also becoming much more common. Is there an inherent link between maternal obesity and gut related diseases in offspring? The fetal stage is critical for gut development and can have long-term effects on the health of the offspring gut. Elevated gut permeability allows the transmission of bacteria, viruses, macromolecules causing gut inflammation, pre-disposing offspring to inflammatory bowel diseases, autoimmune diseases and food allergy. Wingless and Int (Wnt)/?-catenin signaling pathway is essential for proper gut development and epithelial barrier function. Very recently, we found that activation of AMP-activated protein kinase (AMPK) enhances ?-catenin stability and its down-stream signaling; meanwhile, we observed that maternal obesity inhibits AMPK activity and impairs offspring gut epithelial barrier function. CENTRAL HYPOTHESIS: Maternal obesity inhibits AMPK activity in fetal gut, which down-regulates ?-catenin mediated signaling pathway and impairs gut development and barrier function in progeny. SPECIFIC AIMS: 1) To evaluate the impact of maternal obesity on AMPK/?-catenin signaling, development and permeability of progeny gut; 2) to assess the isoform- specific effect of AMPK on fetal and offspring gut development and barrier function. APPROACH: We plan to use our well established maternal obese mouse model, AMPK isoform-specific conditional knockout mice, as well as ex vivo epithelium cultures and in vitro cell cultures for proposed studies. OBJECTIVE: To examine the role of AMPK in fetal and neonatal gut development and permeability under maternal obese condition and to further explore the underlying mechanisms. INNOVATION: We are pioneering studies to define the role of AMPK in animal development. The proposed work is novel, because the effects of AMPK and its associated signaling pathways on gut development have not been studied. ENVIRONMENT: All methodologies required have established in the PI's laboratory. The funding of this project will further strengthen biomedical research component in our department, which will stimulate students' interests in biomedical research and provide students with hands-on experience, facilitating the training of next generation biomedical scientists. IMPACT: Proposed studies will demonstrate that AMPK plays a critical role in linking maternal obesity with gut development and permeability in progeny, which will make it possible to use numerous available anti-diabetic drugs, known activators of AMPK, to improve offspring gut function impaired by maternal obesity. Given the importance of gut barrier function in health, such intervention will help the increasing number of obese mothers in this country to deliver healthy children.