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The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity
Thesis (PhD (Medical Immunology))--University of Pretoria, 2023.
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University of Pretoria
2023
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| access_status_str | Open Access |
| author2 | Ambele, Melvin |
| author_browse | Ambele, Melvin |
| author_facet | Ambele, Melvin |
| collection | Thesis |
| dc_rights_str_mv | © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD (Medical Immunology))--University of Pretoria, 2023. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/92132 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:40:15.382Z |
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| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/92132 The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity Ambele, Melvin u10228188@tuks.co.za Pepper, Michael Sean Pitere, Reabetswe UCTD SLC7A8 Obesity Adipose tissue Adipogenesis Health theses SDG-03 SDG-03: Good health and well-being Thesis (PhD (Medical Immunology))--University of Pretoria, 2023. Obesity is a pandemic affecting both adults and children with an increasing annual prevalence. Adipogenesis, a process in which adipocyte precursors differentiate into mature adipocytes, is considered an important process in identifying molecular determinants that could be targeted to modulate lipid accumulation and adipocyte hypertrophy, thereby combating obesity. Over the past two decades various studies have been conducted to investigate genes that are central to the adipogenesis process. The one limitation has been that most of the studies used animal models and cell lines for this purpose which may possibly be different to how the process is regulated in humans. To overcome this challenge, Ambele et al., 2016 performed an in vitro transcriptome analysis of human adipose-derived stromal cells (ASCs) undergoing adipogenic differentiation. Various genes at various phases of differentiation were identified but one gene of interest was the SLC7A8 which was transiently expressed and was highly upregulated in the early phases of adipogenesis. The SLC7A8 gene encodes LAT2 which is a neutral amino acid transporter. It belongs to a superfamily of proteins that have been implicated in obesity and/or adipogenesis. Since SLC7A8 had not been previously described in the context of adipogenesis and obesity, -it was necessary to elucidate its function in this context using a murine model of diet-induced obesity (DIO). Wildtype and knockout Slc7a8 mice fed on high-fat and control diets were monitored over a 14-week period and various analyses were performed at different time points. Further, human fASCs were differentiated into mature adipocytes in the presence/absence of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of LAT2/SLC7A8. The results obtained from the study showed that in conditions of DIO, Slc7a8 knockout mice had significantly reduced weight gain, improved glucose tolerance, reduced inflammation due to macrophage infiltration and decreased adipocyte hypertrophy in different adipose depots when compared with the wildtype. Lipid accumulation in other peripheral non-lipid storage tissues and organs such as the liver was reduced in the knockout model. Further, the possible mechanism of hypotrophy prevention in Slc7a8 knockout mice was investigated by measuring the expression of genes involved in lipid transport and metabolism and the effect on different plasma metabolites. The observations demonstrated that attenuation of adipocyte hypertrophy in knockout mice differed across the adipose tissue depots, i.e., hypotrophy in the perigonadal (pWAT) and brown adipose tissues (BAT) is due to increased lipolysis, in addition to browning (in BAT), with reduced lipid uptake in the mesenteric adipose tissue (mWAT). Adipocyte hypotrophy in Slc7a8 knockout mice resulted to a significantly lower and higher leptin and adiponectin levels, respectively, as well as reduced plasma levels of the proinflammatory cytokines IL-α, IL-6, IL-7, MIP-1α, and elevated levels of the anti-inflammatory cytokines IL-5, IL-13, and G-CSF in comparison to the wildtype. The inhibition of SLC7A8 function in human ASCs undergoing adipogenic differentiation led to reduced adipogenic capacity with a reduction in lipid droplet formation in mature adipocytes. This was accompanied by downregulation of important adipogenic genes such as PPARϒ, FABP4 and CD36 in response to SLC7A8 function inhibition. Moreover, the timing of inhibition of SLC7A8 function appeared to be critical as inhibition on the day of induction (day 0) suppressed white adipogenesis while inhibition on day 3 post adipogenic induction both suppressed white adipogenesis and promoted white adipose tissue browning activity through increase expression of PRDM16. Overall, this study demonstrates that SLC7A8 is important in obesity development and that its function is important in the production and maturation of adipocytes. Furthermore, the results suggest that SLC7A8 may serve as a potential therapeutic target for anti-obesity drug development with great promise for improving metabolic health. National Research Foundation grant no. 114044. National Health Laboratory Services grant no. 94865. South African Medical Research Council University Flagship Project (SAMRC-RFA-UFSP-01-2013/STEM CELLS). SAMRC Extramural Unit for Stem Cell Research and Therapy Institute for Cellular and Molecular Medicine of the University of Pretoria Immunology PhD (Medical Immunology) Unrestricted 2023-08-31T13:48:00Z 2023-08-31T13:48:00Z 2023-09-08 2023 Thesis * S2023 http://hdl.handle.net/2263/92132 en © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD SLC7A8 Obesity Adipose tissue Adipogenesis Health theses SDG-03 SDG-03: Good health and well-being The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity |
| title | The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity |
| title_full | The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity |
| title_fullStr | The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity |
| title_full_unstemmed | The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity |
| title_short | The role of Solute Carrier Family 7 Member 8 (SLC7A8) in adipogenesis in vitro and in a murine model of obesity |
| title_sort | role of solute carrier family 7 member 8 slc7a8 in adipogenesis in vitro and in a murine model of obesity |
| topic | UCTD SLC7A8 Obesity Adipose tissue Adipogenesis Health theses SDG-03 SDG-03: Good health and well-being |
| url | http://hdl.handle.net/2263/92132 |