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Author ORCID Identifier
Campus-Only Access for One (1) Year
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Nutritional and Metabolic Diseases
Obesity is a serious health problem in the U.S. and worldwide and is associated with non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Observational studies have also shown an inverse relationship between obesity and reduced bioavailability of fat-soluble vitamins, which is due in part to increased sequestration in expanded adipose tissue (AT). AT serves as the primary site of storage organ for excess energy, however, in morbid obesity enlarged adipocytes exhibit decreased lipid uptake, impaired lipid hydrolysis and oxidation and increased inflammation, which are collectively referred to as AT dysfunction. Substantial evidence characterizes AT dysfunction as a central mechanism leading to the development of metabolic comorbidities, such as chronic inflammation, hepatic steatosis, and insulin resistance. However, there is very little information regarding the molecular mechanisms that mediate AT dysfunction in obesity. Moreover, there are few intervention approaches and treatment options against AT dysfunction.
Through the dissertation work, we have identified four dietary bioactives that mitigate obesity-induced AT dysfunction, including extracts from aronia berries and cranberries, sulforaphane and formononetin, with potential underlying mechanisms identified for each bioactive using in vivo and/or in vitro models. In addition, using C57BL/6 mice with a genetic knockout of tumor necrosis factor alpha (TNFα KO), we have characterized the impact of the genetic ablation of TNFα, a potent mediator of tissue and systemic inflammation, on fatty acid metabolism and inflammation in AT and the liver during the development of a high-fat diet (HFD)-induced obesity. We found that TNFα KO mitigates HFD-induced impairments of lipid hydrolysis and fatty acid oxidation (FAO) and expression of inflammatory markers in AT with concomitant improvements of adiposity, hepatic steatosis, and insulin resistance in these mice. This suggests that obesity-induced TNFα serves as a potential mediator of AT dysfunction. Furthermore, our in vivo and in vitro findings indicate that TNFα downregulates the expression of genes related to FAO in adipocytes by suppressing the conversion of retinol (dietary vitamin A) to retinoic acid (RA), which is a potential endogenous agonist of the transcriptional factor peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) for inducing genes related to FAO. The treatment of exogenous RA, on the other hand, significantly increased adipocyte FAO in TNFα-treated 3T3-L1 adipocytes. RA treatment also suppressed the expression of pro-inflammatory genes in RAW264.7 macrophages stimulated with adipocyte-conditioned media by increasing PPARβ/δ protein expression in both cell types.
Taken together, these findings provide a biochemical and molecular basis for planning future studies to test clinical relevance and also for developing therapeutic interventions against obesity-induced AT dysfunction and related metabolic complications.
Yu, Seok-Yeong and Yu, Seok-Yeong, "POTENTIAL BIOACTIVES AND INFLAMMATORY MEDIATORS REGULATING ADIPOSE TISSUE FUNCTION IN OBESITY" (2021). Doctoral Dissertations. 2151.
Available for download on Tuesday, February 01, 2022