Obesity is associated with a state of adipose tissue dysfunction characterized by increased inflammation and aberrant metabolism that underlies systemic metabolic disease. Hypoxia is a putative root cause of adipose tissue dysfunction in obesity. Our preliminary data demonstrate that hypoxia induces inflammation in human adipose tissue macrophages (ATM) and hexosamine biosynthesis (HBS) and lipogenesis in human adipocytes, and that endoplasmic reticulum stress (ERS) and stress-activated protein kinases (SAPK) regulate these processes. Our long-term goal is to develop novel cell-based therapy for metabolic disease based on genetic modification of adipocytes and ATM. Our proposal-specific goals are to define the effects of hypoxia on human adipocyte metabolism and ATM inflammatory responses, to define the role of ERS and SAPK activation in regulating these processes, to define the role of ATM in regulating adipocyte metabolism, and finally, to determine if genetic modification of human adipocytes and ATM to accomplish knockdown of HBS and SAPK- related molecules shifts adipocytes towards a favorable metabolic phenotype. Our central hypotheses are: that hypoxia induces metabolic dysfunction characterized by increased lipogenesis and HBS in adipocytes, directly as well as via hypoxia-induced ATM inflammation;that these processes are regulated by ERS and SAPK activation;and that genetic knockdown of HBS-related mediators in adipocytes and SAPK-related mediators in ATM will induce a favorable metabolic phenotype in adipocytes.
Aim I will define the role of hypoxia in regulating ERS and metabolism in human adipocytes and determine if inhibition of HBS attenuates hypoxia- induced ERS and metabolic responses in adipocytes.
Aim II will define the role of hypoxia in regulating human ATM inflammation and determine if SAPK mediator knockdown attenuates hypoxia-induced ATM inflammatory responses.
Aim III will define the role of hypoxia-primed ATM in regulating adipocyte metabolism and determine if SAPK mediator knockdown in ATM attenuates hypoxia's effects on adipocyte metabolism. This proposal is significant because it will identify novel hypoxia-inducible mediators and mechanisms of adipose tissue dysfunction in human tissues that will lead to therapy for metabolic disease. This proposal is innovative because it develops a model system for genetic modification of human adipocytes and ATM with the goal of manipulating adipocytes towards a favorable metabolic phenotype.
Obesity is a public health crisis and adipose tissue dysfunction underlies obesity-related diseases. Hypoxia is an important underlying cause of adipose tissue dysfunction. This proposal studies the role of hypoxia in regulating human adipose tissue inflammation and metabolism and will develop methods to genetically alter human adipocytes by targeting hypoxia-inducible molecules in order to shift adipocytes towards a metabolically favorable phenotype as a first step towards developing adipocyte-directed gene therapy for metabolic disease.
|O'Rourke, Robert W; Johnson, Geoffrey S; Purnell, Jonathan Q et al. (2018) Serum biomarkers of inflammation and adiposity in the LABS cohort: associations with metabolic disease and surgical outcomes. Int J Obes (Lond) :|
|Muir, Lindsey A; Kiridena, Samadhi; Griffin, Cameron et al. (2018) Frontline Science: Rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages. J Leukoc Biol 103:615-628|
|O'Rourke, Robert W (2018) Adipose tissue and the physiologic underpinnings of metabolic disease. Surg Obes Relat Dis 14:1755-1763|
|Baker, Nicki A; Muir, Lindsey A; Washabaugh, Alexandra R et al. (2017) Diabetes-Specific Regulation of Adipocyte Metabolism by the Adipose Tissue Extracellular Matrix. J Clin Endocrinol Metab 102:1032-1043|
|Muir, Lindsey A; Baker, Nicki A; Washabaugh, Alexandra R et al. (2017) Adipocyte hypertrophy-hyperplasia balance contributes to weight loss after bariatric surgery. Adipocyte 6:134-140|
|Frikke-Schmidt, Henriette; Zamarron, Brian F; O'Rourke, Robert W et al. (2017) Weight loss independent changes in adipose tissue macrophage and T cell populations after sleeve gastrectomy in mice. Mol Metab 6:317-326|
|Baker, Nicki A; Muir, Lindsey A; Lumeng, Carey N et al. (2017) Differentiation and Metabolic Interrogation of Human Adipocytes. Methods Mol Biol 1566:61-76|
|Morris, David L; Oatmen, Kelsie E; Mergian, Taleen A et al. (2016) CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity. J Leukoc Biol 99:1107-19|
|Meyer, Kevin A; Neeley, Christopher K; Baker, Nicki A et al. (2016) Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer. Biochem Biophys Rep 7:144-149|
|Muir, Lindsey A; Neeley, Christopher K; Meyer, Kevin A et al. (2016) Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity. Obesity (Silver Spring) 24:597-605|
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