The role of CH25H in adipose tissue - a new potential target in anti-obesity therapy?
The role of CH25H in adipose tissue - a new potential target in anti-obesity therapy?
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DissertationPrüfungsdatum
14.06.2024Datum der Veröffentlichung
25.06.2024Erstgutachter
Pfeifer, AlexanderZweitgutachter
Sasse, PhilippMetadaten
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Inhalt
Obesity associates with comorbidities as hypertension, cardiovascular disease, metabolic syndrome and type 2 diabetes mellitus and therefore depicts an emerging health issue. On a molecular level, obesity is accompanied by a chronic inflammation of adipose tissue resulting from invading immune cells and local cytokine production leading to the mentioned systemic immunometabolic disorders.
7α,25-dihydroxycholesterol is a bioactive oxysterol mainly synthesised enzymatically via the enzymes CH25H and CYP7B1, is degraded by the enzyme HSD3B7 and is a potent activator of EBI2 – an inhibitory G-protein-coupled receptor predominantly involved in immune regulation. Our preliminary findings showed that 7α,25-dihydroxycholesterol can be produced in adipose tissue and influences adipose tissue metabolism, but its source in adipose tissue is unclear.
Based on Polymerase Chain Reaction data from CH25H, CYP7B1 and HSD3B7 in adipose tissue fractions and co-cultivation experiments of brown adipocytes with macrophages, endothelial cells and fibroblasts, I propose in conjunction with findings of other groups that 7α,25-dihydroxycholesterol is mainly produced by macrophages in adipose tissues.
The functional role of CH25H was studied in a genetic Ch25h knock out mouse model. Initially, oxysterol levels were measured spectrometrically in serum, liver and adipose tissues of Ch25h wild type and knock out mice. There was no difference in 7α,25-dihydroxycholesterol levels between wild type and knock out mice but due to an altered expression pattern of other oxysterols there might be a compensatory mechanism for 7α,25-dihydroxycholesterol production in adipose tissue.
Functionally, Ch25h knock out mice in standard housing conditions had higher lipolytic capacities especially in brown adipose tissue in ex vivo lipolysis. Furthermore, after one week of chronic cold exposure at 4 °C, Ch25h knock out mice had higher energy expenditure and significantly more brown adipose tissue mass compared to wild type mice. Based on these findings I hypothesise that Ch25h knock out mice are enabled to perform lipolysis and non-shivering thermogenesis better than wild type mice because 7α,25-dihydroxycholesterol as an inhibitor of lipolysis is missing.
To study the effect of Ch25h deficiency in obesity, Ch25h wild type and knock out mice were fed with normal diet and high fat diet for 12 weeks. I could demonstrate that Ch25h knock out mice have higher energy expenditure with more expression of Uncoupling Protein 1 in normal diet and significantly better glucose homeostasis in Glucose Tolerance Test indicating that lack of CH25H ameliorates obesity-related comorbidities.
The data provided by this thesis suggest that CH25H plays an important role in the metabolic regulation of adipose tissue in physiological as well as in pathophysiological conditions, thus rendering CH25H and its products an interesting target in the treatment of metabolic disorders.
7α,25-dihydroxycholesterol is a bioactive oxysterol mainly synthesised enzymatically via the enzymes CH25H and CYP7B1, is degraded by the enzyme HSD3B7 and is a potent activator of EBI2 – an inhibitory G-protein-coupled receptor predominantly involved in immune regulation. Our preliminary findings showed that 7α,25-dihydroxycholesterol can be produced in adipose tissue and influences adipose tissue metabolism, but its source in adipose tissue is unclear.
Based on Polymerase Chain Reaction data from CH25H, CYP7B1 and HSD3B7 in adipose tissue fractions and co-cultivation experiments of brown adipocytes with macrophages, endothelial cells and fibroblasts, I propose in conjunction with findings of other groups that 7α,25-dihydroxycholesterol is mainly produced by macrophages in adipose tissues.
The functional role of CH25H was studied in a genetic Ch25h knock out mouse model. Initially, oxysterol levels were measured spectrometrically in serum, liver and adipose tissues of Ch25h wild type and knock out mice. There was no difference in 7α,25-dihydroxycholesterol levels between wild type and knock out mice but due to an altered expression pattern of other oxysterols there might be a compensatory mechanism for 7α,25-dihydroxycholesterol production in adipose tissue.
Functionally, Ch25h knock out mice in standard housing conditions had higher lipolytic capacities especially in brown adipose tissue in ex vivo lipolysis. Furthermore, after one week of chronic cold exposure at 4 °C, Ch25h knock out mice had higher energy expenditure and significantly more brown adipose tissue mass compared to wild type mice. Based on these findings I hypothesise that Ch25h knock out mice are enabled to perform lipolysis and non-shivering thermogenesis better than wild type mice because 7α,25-dihydroxycholesterol as an inhibitor of lipolysis is missing.
To study the effect of Ch25h deficiency in obesity, Ch25h wild type and knock out mice were fed with normal diet and high fat diet for 12 weeks. I could demonstrate that Ch25h knock out mice have higher energy expenditure with more expression of Uncoupling Protein 1 in normal diet and significantly better glucose homeostasis in Glucose Tolerance Test indicating that lack of CH25H ameliorates obesity-related comorbidities.
The data provided by this thesis suggest that CH25H plays an important role in the metabolic regulation of adipose tissue in physiological as well as in pathophysiological conditions, thus rendering CH25H and its products an interesting target in the treatment of metabolic disorders.
Schlagwörter
CH25H, EBI2, Oxysterole, Adipositas, 7α,25-dihydroxycholesterol, Fettgewebe, obesity, oxysterols, adipose tissue
Klassifikation (DDC)
500 Naturwissenschaften 570 Biowissenschaften, Biologie 610 Medizin, Gesundheit 615 Pharmakologie, TherapeutikSchleis, Inna: The role of CH25H in adipose tissue - a new potential target in anti-obesity therapy?. - Bonn, 2024. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-76683
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-76683
@phdthesis{handle:20.500.11811/11618,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-76683,
author = {{Inna Schleis}},
title = {The role of CH25H in adipose tissue - a new potential target in anti-obesity therapy?},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2024,
month = jun,
note = {Obesity associates with comorbidities as hypertension, cardiovascular disease, metabolic syndrome and type 2 diabetes mellitus and therefore depicts an emerging health issue. On a molecular level, obesity is accompanied by a chronic inflammation of adipose tissue resulting from invading immune cells and local cytokine production leading to the mentioned systemic immunometabolic disorders.
7α,25-dihydroxycholesterol is a bioactive oxysterol mainly synthesised enzymatically via the enzymes CH25H and CYP7B1, is degraded by the enzyme HSD3B7 and is a potent activator of EBI2 – an inhibitory G-protein-coupled receptor predominantly involved in immune regulation. Our preliminary findings showed that 7α,25-dihydroxycholesterol can be produced in adipose tissue and influences adipose tissue metabolism, but its source in adipose tissue is unclear.
Based on Polymerase Chain Reaction data from CH25H, CYP7B1 and HSD3B7 in adipose tissue fractions and co-cultivation experiments of brown adipocytes with macrophages, endothelial cells and fibroblasts, I propose in conjunction with findings of other groups that 7α,25-dihydroxycholesterol is mainly produced by macrophages in adipose tissues.
The functional role of CH25H was studied in a genetic Ch25h knock out mouse model. Initially, oxysterol levels were measured spectrometrically in serum, liver and adipose tissues of Ch25h wild type and knock out mice. There was no difference in 7α,25-dihydroxycholesterol levels between wild type and knock out mice but due to an altered expression pattern of other oxysterols there might be a compensatory mechanism for 7α,25-dihydroxycholesterol production in adipose tissue.
Functionally, Ch25h knock out mice in standard housing conditions had higher lipolytic capacities especially in brown adipose tissue in ex vivo lipolysis. Furthermore, after one week of chronic cold exposure at 4 °C, Ch25h knock out mice had higher energy expenditure and significantly more brown adipose tissue mass compared to wild type mice. Based on these findings I hypothesise that Ch25h knock out mice are enabled to perform lipolysis and non-shivering thermogenesis better than wild type mice because 7α,25-dihydroxycholesterol as an inhibitor of lipolysis is missing.
To study the effect of Ch25h deficiency in obesity, Ch25h wild type and knock out mice were fed with normal diet and high fat diet for 12 weeks. I could demonstrate that Ch25h knock out mice have higher energy expenditure with more expression of Uncoupling Protein 1 in normal diet and significantly better glucose homeostasis in Glucose Tolerance Test indicating that lack of CH25H ameliorates obesity-related comorbidities.
The data provided by this thesis suggest that CH25H plays an important role in the metabolic regulation of adipose tissue in physiological as well as in pathophysiological conditions, thus rendering CH25H and its products an interesting target in the treatment of metabolic disorders.},
url = {https://hdl.handle.net/20.500.11811/11618}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-76683,
author = {{Inna Schleis}},
title = {The role of CH25H in adipose tissue - a new potential target in anti-obesity therapy?},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2024,
month = jun,
note = {Obesity associates with comorbidities as hypertension, cardiovascular disease, metabolic syndrome and type 2 diabetes mellitus and therefore depicts an emerging health issue. On a molecular level, obesity is accompanied by a chronic inflammation of adipose tissue resulting from invading immune cells and local cytokine production leading to the mentioned systemic immunometabolic disorders.
7α,25-dihydroxycholesterol is a bioactive oxysterol mainly synthesised enzymatically via the enzymes CH25H and CYP7B1, is degraded by the enzyme HSD3B7 and is a potent activator of EBI2 – an inhibitory G-protein-coupled receptor predominantly involved in immune regulation. Our preliminary findings showed that 7α,25-dihydroxycholesterol can be produced in adipose tissue and influences adipose tissue metabolism, but its source in adipose tissue is unclear.
Based on Polymerase Chain Reaction data from CH25H, CYP7B1 and HSD3B7 in adipose tissue fractions and co-cultivation experiments of brown adipocytes with macrophages, endothelial cells and fibroblasts, I propose in conjunction with findings of other groups that 7α,25-dihydroxycholesterol is mainly produced by macrophages in adipose tissues.
The functional role of CH25H was studied in a genetic Ch25h knock out mouse model. Initially, oxysterol levels were measured spectrometrically in serum, liver and adipose tissues of Ch25h wild type and knock out mice. There was no difference in 7α,25-dihydroxycholesterol levels between wild type and knock out mice but due to an altered expression pattern of other oxysterols there might be a compensatory mechanism for 7α,25-dihydroxycholesterol production in adipose tissue.
Functionally, Ch25h knock out mice in standard housing conditions had higher lipolytic capacities especially in brown adipose tissue in ex vivo lipolysis. Furthermore, after one week of chronic cold exposure at 4 °C, Ch25h knock out mice had higher energy expenditure and significantly more brown adipose tissue mass compared to wild type mice. Based on these findings I hypothesise that Ch25h knock out mice are enabled to perform lipolysis and non-shivering thermogenesis better than wild type mice because 7α,25-dihydroxycholesterol as an inhibitor of lipolysis is missing.
To study the effect of Ch25h deficiency in obesity, Ch25h wild type and knock out mice were fed with normal diet and high fat diet for 12 weeks. I could demonstrate that Ch25h knock out mice have higher energy expenditure with more expression of Uncoupling Protein 1 in normal diet and significantly better glucose homeostasis in Glucose Tolerance Test indicating that lack of CH25H ameliorates obesity-related comorbidities.
The data provided by this thesis suggest that CH25H plays an important role in the metabolic regulation of adipose tissue in physiological as well as in pathophysiological conditions, thus rendering CH25H and its products an interesting target in the treatment of metabolic disorders.},
url = {https://hdl.handle.net/20.500.11811/11618}
}
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