The role of Dicer in adipocyte differentiation and metabolism
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Date
2024-01-11
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Dissertation
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Abstract
With regard to the increasing global prevalence of obesity, there is a tremendous need to further
delineate metabolic processes to identify potential targets for future treatment options. This being said, Dicer is a well-studied enzyme in miRNA biogenesis, that was additionally shown to have implications in metabolic processes [63,66,69,80]. Although its role has been intensively examined in AT of mice, its metabolic importance remains rather unclear in the human setting. This study provides strong evidence that Dicer is a crucial factor in human AT metabolism as its relative absence affected cellular glucose uptake in human pre-/adipocytes to an enormous extent. In particular, Dicer deficient cells revealed remarkably diminished glucose uptake capacity, as shown in two different human model systems. Additional proof was offered by chemical induction of Dicer activity via enoxacin which generated the opposite effects to the LOF approach. Furthermore, the impairment in glucose incorporation was even more prominent in preadipocytes, whereas treatment with BAY 876 was able to vanish metabolic alterations. This led to the identification of GLUT1 as key regulator in this metabolic phenotype. In contrast to previous scientific reports, we described that Dicer KD does not seem to have a crucial role in preadipocyte-to-adipocyte differentiation, at least not in the human cell model system, as evaluated in SGBS and hMADS cells. Yet, interestingly, and very much like in the murine situation, Dicer deficient cells appeared to favor a preferably white phenotype. That is, cellular UCP1 levels were comparably low, whereas WAT associated leptin abundance increased. However, this phenotype was not demonstrated to have any functional relevance as cellular respiration remained unaffected. This was particularly shown by unchanged mitochondrial content and unaltered oxygen consumption upon siRNA mediated Dicer KD. The expectation was that intrinsic miRNA levels might be the reason for the cellular phenotypes observed. Surprisingly, miRNA sequencing data only showed few miRNAs to be altered, including miR-543 and miR-18a-3p. Investigation of these two miRNAs in metabolic assays did not lead to the identification of the key mediator miRNA which is responsible for inducing decreased lycolytic activity in human SGBS cells. In summary, this work underlined the importance of Dicer as a promising target molecule in metabolic processes. Future studies should further focus on identifying how Dicer mediates glucose uptake in pre-/adipocytes in order to create new strategies for obesity treatment.
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Faculties
Medizinische Fakultät
Institutions
UKU. Klinik für Kinder- und Jugendmedizin
Institut für Molekulare Endokrinologie der Tiere
Institut für Molekulare Endokrinologie der Tiere
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DFG Project uulm
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Lizenz B (ohne Print-on-Demand)
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DFG Project THU
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Keywords
Fettsucht, Insulinresistenz, miRNS, Obesity, Adipose tissue, Adipogenesis, MicroRNAs, DDC 610 / Medicine & health