Developmental and nutritional regulation of lipid metabolism

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

PROJECT SUMMARY Cells respond to their environment by detecting extracellular signals that dictate how energy resources, including lipids, are utilized. In complex tissues, cells with specialized metabolic functions perceive developmental, nutritional, and environmental inputs that strictly control the allocation of lipids into different metabolic pathways to maintain organismal energy homeostasis. Dysregulation of these pathways can lead to metabolic diseases or cancer. Pro-growth signal transduction pathways, including the mTOR Complex 2 (mTORC2) and MAP Kinase pathways, promote growth while influencing metabolic decisions; however, the upstream regulators and downstream effectors of these pathways that control lipid homeostasis remain largely unknown. We have found that the Hedgehog morphogen, a classic regulator of developmental pattering and growth, engages mTORC2 signaling to govern lipid homeostasis in C. elegans and mammalian cells. The first goal of this project is to elucidate the molecular mechanisms that mediate the cross-talk between these two pro-growth pathways and define how they function together to govern lipid homeostasis. Leveraging the power of forward genetic screens, we have identified new positive regulators of the Hedgehog-mTORC2 signaling axis. We will define how these factors promote Hedgehog-mTORC2 cross-talk using interdisciplinary approaches in C. elegans and mammalian cells. Additionally, we have found that MAPK signaling acts in concert with mTORC2 in the C. elegans intestine to maintain lipid homeostasis. MAP Kinases, which function broadly in stress responses and cell proliferation, are crucial for maintaining cellular homeostasis; however, how MAPK signaling controls lipid metabolism pathways is poorly understood. We found that two MEKK3-like proteins are required for proper nutrient uptake in the intestine. Using forward genetic approaches, we have identified candidate downstream effectors of MAPK signaling that control nutrient absorption. The second goal of this project is to define the mechanism by which MAPK signaling regulates the absorption of nutrients in the intestine. The long-term objective of these two projects is to uncover new regulatory factors of pro-growth signal transduction pathways and to elucidate the molecular mechanisms by which they exert metabolic control. In addition to developmental regulators, cellular metabolism can be shaped by environmental and nutritional cues that engage pro-growth and nutrient sensing pathways, including the mTOR and AMPK pathways, to dictate how lipids are utilized. We have demonstrated that acetic-acid producing microbes within the gut microbiome reconfigure intestinal lipid metabolism pathways to stimulate a fasting-like response in the host, resulting in loss of fat stores. The third goal of this project is to define the mechanisms by which metabolites from these gut microbes engage host homeostatic signaling pathways, resulting in reduced lipid accumulation. Together, this research will shed light on how developmental and nutritional signals interface with pro-growth and homeostatic signaling pathways to shape the metabolic function of specialized cells.