Campitelli, Michele (2021) NUTRACEUTICALS IN ADIPOSE TISSUE DYSFUNCTION: LESSONS FROM CITRUS AURANTIUM L. DRY EXTRACT. [Tesi di dottorato]

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Abstract

Abstract Metabolic and/or endocrine dysfunction of the white adipose tissue contributes to the development of metabolic disorders, such as Type 2 Diabetes and other pathologies, like atherosclerosis and cardiovascular disease. Therefore, the identification of products able to improve adipose tissue function represents a valuable strategy for the prevention and/or treatment of these disorders. The aim of this study was to investigate whether a nutraceutical compound obtained from Citrus Aurantium L. fruit juice (CAde) might regulate adipocyte differentiation and function in vitro, elucidate the underlying molecular mechanism through which CAde may exert its function and evaluate whether it might be effective against micro-environmental insults, which affect adipogenesis and adipose tissue function. The following results have been obtained in two separate studies. Study 1: CAde enhances terminal adipocyte differentiation of 3T3-L1 cells raising the expression of CCAAT/enhancer binding protein beta (C/ebpβ), peroxisome proliferator activated receptor gamma (Pparγ), glucose transporter type 4 (Glut4) and fatty acid binding protein 4 (Fabp4). CAde improves insulininduced glucose uptake of 3T3-L1 adipocytes, as well. A focused analysis of the phases occurring in the differentiation process from pre- adipocytes into mature adipocytes furthermore revealed that CAde promotes the early differentiation stage by anticipating the 3T3-L1 cell cycle entry and progression during mitotic clonal expansion. Study 2: CAde enhanced the early adipogenesis phases by down-regulating miR-155 expression and increasing both C/ebpβ and cAMP response elementbinding protein (Creb) mRNA and protein levels. Also, CAde prevented the antiadipogenic effects of the Tumor necrosis factor alpha (TNFα) by improving adipocyte differentiation and restoring miR-155 and C/ebpβ and Creb gene expression respectively, at early time points in cells exposed to TNFα. In conclusion, in my PhD thesis I revealed the nutraceutical properties of CAde on the fat cell functional capacity in terms of enhanced adipocyte differentiation and function in vitro. I also demonstrated that the downregulation of the miR-155, which causes the up-regulation of the target genes, C/ebpβ and Creb, is part of the mechanism through which CAde enhances adipocyte differentiation of pre-adipocytes in vitro. Furthermore, I provided substantial evidence of the efficacy of CAde against micro-environment insults, which are harmful to adipose cell functionality. These data suggest that the development of nutraceutical products derived from CAde may be an effective strategy for treating adipocyte dysfunction and its related disorders.

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