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Obesity and related co-morbidities are a health emergency. Our current understanding of the mechanisms behind obesity and lipotoxicity is based on the “Energy Balance Model” (EBM) of obesity wherein the focus has centered on the imbalance between energy intake (calories) and energy expenditure (physical activity). However, the EBM of obesity does not account for the impact of water homeostasis on lipid metabolism. The breakdown of lipids via beta oxidation yields about 100 g of water for every 100 g of fat. Thus, in the appropriate context, in addition to energy, adipose tissue can be considered a water reservoir. In fact, metabolic water is critical for the survival of animals that live in environments where access to fresh water is limited. Marine mammals do not consume sea water, rather they rely on metabolic water production for the maintenance of water homeostasis. Based on recent data from our laboratory, the overall goal this proposal is to understand the molecular mechanisms, signaling pathways, and physiological feedback loops that underpin the water-fat metabolism axis at the single cell and whole organism level. Despite a robust independent literature on both the response to hypertonic stress and de novo lipogenesis, the interaction between water and fat in health and disease is unknown. This is a tremendous gap in knowledge that can only be tackled using cross disciplinary approaches and requires a thorough understanding of both water and metabolic physiology. Based on our groundbreaking hypothesis, coupled with novel methodologies and physiologic frameworks we will identify the mechanisms through which cells and organisms regulate lipid synthesis in response to hypertonic stress. Specifically, we will study how single cells and organisms regulate lipid synthesis and breakdown in response to varied stressors and conditions. Understanding how water homeostasis and lipid homeostasis work simultaneously and operate in a coordinated fashion at the single cell level and the whole organism level will lead to a paradigm-shift in our understanding of how cells and organisms interact with their environment in both health and disease.
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