Mechanisms of Regulation of Retinoic Acid Homeostasis

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Obesity is a major public health problem with 38% of American adults being obese and rates of obesity increasing dramatically worldwide. It is estimated that obesity is second only to smoking as a cause of premature preventable death. This is largely due to the comorbidities associated with obesity including metabolic syndrome, diabetes, cardiovascular disease and nonalcoholic fatty liver disease. Yet, very little progress has been made in the development of treatments to prevent obesity and its comorbidities, and the mechanistic link between obesity and development of comorbidities is not completely understood. Several studies have shown that obese rodents develop tissue vitamin A deficiency, with tissue retinoid concentrations decreasing by a stunning 75-90%, suggesting profound metabolic dysregulation. Findings in cell systems and animal models demonstrate that retinoids regulate adipocyte differentiation and glucose and lipid metabolism and, further, that decreased retinoid concentrations are associated with progressive obesity, insulin resistance and glucose intolerance. Thus, aggregate preclinical data suggest that altered vitamin A metabolism may contribute directly to obesity progression and the development of obesity-related co-morbidities. Critically, the mechanisms underlying this dysregulated vitamin A metabolism remain poorly understood, and the relevance of these preclinical findings to human obesity is unclear. A central premise of this proposal is that altered vitamin A metabolism in obesity is a result of increased inflammatory cytokines (IL-1, IL-6 and TNF in metabolic tissues, which regulate the expression of the retinoid metabolizing enzymes CYP26, LRAT, ALDH1A and RDH in adipocytes and various liver cell types. We further hypothesize that this dysregulation of vitamin A metabolism occurs in human obesity as well as in animal models. We will test our hypotheses in two specific aims: 1) to identify the enzymes and the key regulatory signals that control all-trans-retinoic acid (atRA) concentrations and vitamin A metabolic flux in human liver and adipose tissue, and 2) to establish whether adipose tissue and liver vitamin A metabolomes are altered in obese humans. We will use our state-of-the-art mass spectrometry methods, innovative metabolic flux experiments and kinetic modeling in specific cell types to characterize the key enzymes that metabolize retinoids in liver and adipose tissue and determine how the activity of these enzymes is altered in obesity. To determine whether tissue retinoids are altered in human obesity, we will conduct a cross sectional clinical study comparing visceral and subcutaneous adipose tissue, liver and serum vitamin A metabolomes in obese and non-obese subjects. The proposed studies will lay the foundation for understanding the regulation of vitamin A metabolism in human liver and adipose tissue and for determing how vitamin A metabolism may become dysregulated in obesity contributing to progressive obesity and its co-morbidities in humans. The results will generate unprecedented insight into human retinoid biology and ultimately could lead to targeted therapeutic interventions designed to restore tissue retinoid signaling as a novel strategy for the treatment of obesity and its sequela.