Pub Date : 2022-12-01DOI: 10.1080/21623945.2022.2104512
Jie Wen, Liwen Wang
Immune cell-mediated adipose tissue (AT) inflammation contributes to obesity-related metabolic disorders, but the precise underlying mechanisms remain largely elusive. In this study, we used the R software to screen key differentially expressed genes (DEGs) in AT from lean and obese individuals and conducted function enrichment analysis. We then analysed their PPI network by using the STRING database. Hub genes were screened by cytohubba plugin. Subsequently, CIBERSORTx was used to predict the proportion of immune cells in AT from lean and obese subjects. Finally, the correlation between hub genes and immune cell proportions was analysed. These studies identified 290 DEGs in the AT between lean and obese subjects. Among them, IL6, CCL19, CXCL8, CXCL12, CCL2, CCL3, CCL4, CXCL2, IL1B, and CXCL1 were proved to be hub genes in regulating the protein-protein interaction (PPI) network. We also found that CXCL8 is positively correlated with resting NK cells, monocytes, activated mast cells, and eosinophils, but negatively correlated with CD8+ T cells and activated NK cells in obese individuals. Taken together, our study identified key genes in AT that are correlated with immune cell infiltration, uncovering potential new targets for the prevention and treatment of obesity and its related complications via regulating the immune microenvironment.
{"title":"Identification of key genes and their association with immune infiltration in adipose tissue of obese patients: a bioinformatic analysis.","authors":"Jie Wen, Liwen Wang","doi":"10.1080/21623945.2022.2104512","DOIUrl":"https://doi.org/10.1080/21623945.2022.2104512","url":null,"abstract":"<p><p>Immune cell-mediated adipose tissue (AT) inflammation contributes to obesity-related metabolic disorders, but the precise underlying mechanisms remain largely elusive. In this study, we used the R software to screen key differentially expressed genes (DEGs) in AT from lean and obese individuals and conducted function enrichment analysis. We then analysed their PPI network by using the STRING database. Hub genes were screened by cytohubba plugin. Subsequently, CIBERSORTx was used to predict the proportion of immune cells in AT from lean and obese subjects. Finally, the correlation between hub genes and immune cell proportions was analysed. These studies identified 290 DEGs in the AT between lean and obese subjects. Among them, <i>IL6, CCL19, CXCL8, CXCL12, CCL2, CCL3, CCL4, CXCL2, IL1B</i>, and <i>CXCL1</i> were proved to be hub genes in regulating the protein-protein interaction (PPI) network. We also found that <i>CXCL8</i> is positively correlated with resting NK cells, monocytes, activated mast cells, and eosinophils, but negatively correlated with CD8<sup>+</sup> T cells and activated NK cells in obese individuals. Taken together, our study identified key genes in AT that are correlated with immune cell infiltration, uncovering potential new targets for the prevention and treatment of obesity and its related complications via regulating the immune microenvironment.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9336476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40550975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.1080/21623945.2022.2102116
Fozia Ahmed, Susanne Hetty, Milica Vranic, Giovanni Fanni, Joel Kullberg, Maria João Pereira, Jan W Eriksson
Oestrogen receptor 2 (ESR2) expression has been shown to be higher in subcutaneous adipose tissue (SAT) from postmenopausal compared to premenopausal women. The functional significance of altered ESR2 expression is not fully known. This study investigates the role of ESR2 for adipose tissue lipid and glucose metabolism. SAT biopsies were obtained from 44 female subjects with or without T2D. Gene expression of ESR2 and markers of adipose function and metabolism was assessed. ESR2 knockdown was performed using CRISPR/Cas9 in preadipocytes isolated from SAT of females, and differentiation rate, lipid storage, and glucose uptake were measured.ESR2 expression was inversely correlated with measures of central obesity and expression of some fatty acid oxidation markers, and positively correlated with lipid storage and glucose transport markers. Differentiation was reduced in ESR2 knockdown preadipocytes. This corresponded to reduced expression of markers of differentiation and lipogenesis. Glucose uptake was reduced in knockdown adipocytes.Our results indicate that ESR2 deficiency in women is associated with visceral adiposity and impaired subcutaneous adipocyte differentiation as well as glucose and lipid utilization. High ESR2 expression, as seen after menopause, could be a contributing factor to SAT expansion. This may support a possible target to promote a healthy obesity phenotype.
{"title":"<i>ESR2</i> expression in subcutaneous adipose tissue is related to body fat distribution in women, and knockdown impairs preadipocyte differentiation.","authors":"Fozia Ahmed, Susanne Hetty, Milica Vranic, Giovanni Fanni, Joel Kullberg, Maria João Pereira, Jan W Eriksson","doi":"10.1080/21623945.2022.2102116","DOIUrl":"https://doi.org/10.1080/21623945.2022.2102116","url":null,"abstract":"<p><p>Oestrogen receptor 2 (<i>ESR2</i>) expression has been shown to be higher in subcutaneous adipose tissue (SAT) from postmenopausal compared to premenopausal women. The functional significance of altered <i>ESR2</i> expression is not fully known. This study investigates the role of <i>ESR2</i> for adipose tissue lipid and glucose metabolism. SAT biopsies were obtained from 44 female subjects with or without T2D. Gene expression of <i>ESR2</i> and markers of adipose function and metabolism was assessed. <i>ESR2</i> knockdown was performed using CRISPR/Cas9 in preadipocytes isolated from SAT of females, and differentiation rate, lipid storage, and glucose uptake were measured.<i>ESR2</i> expression was inversely correlated with measures of central obesity and expression of some fatty acid oxidation markers, and positively correlated with lipid storage and glucose transport markers. Differentiation was reduced in <i>ESR2</i> knockdown preadipocytes. This corresponded to reduced expression of markers of differentiation and lipogenesis. Glucose uptake was reduced in knockdown adipocytes.Our results indicate that <i>ESR2</i> deficiency in women is associated with visceral adiposity and impaired subcutaneous adipocyte differentiation as well as glucose and lipid utilization. High <i>ESR2</i> expression, as seen after menopause, could be a contributing factor to SAT expansion. This may support a possible target to promote a healthy obesity phenotype.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9387337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40608992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.1080/21623945.2022.2073854
Helen M M Waddell, Matthew K Moore, Morgan A Herbert-Olsen, Martin K Stiles, Rexson D Tse, Sean Coffey, Regis R Lamberts, Hamish M Aitken-Buck
Predictors of overall epicardial adipose tissue deposition have been found to vary between males and females. Whether similar sex differences exist in epicardial fat cell morphology is currently unknown. This study aimed to determine whether epicardial fat cell size is associated with different clinical measurements in males and females. Fat cell sizes were measured from epicardial, paracardial, and appendix adipose tissues of post-mortem cases (N= 118 total, 37 females). Epicardial, extra-pericardial, and visceral fat volumes were measured by computed tomography from a subset of cases (N= 70, 22 females). Correlation analyses and stepwise linear regression were performed to identify predictors of fat cell size in males and females. Median fat cell sizes in all depots did not differ between males and females. Body mass index (BMI) and age were independently predictive of epicardial, paracardial, and appendix fat cell sizes in males, but not in females. Epicardial and appendix fat cell sizes were associated with epicardial and visceral fat volumes, respectively, in males only. In females, paracardial fat cell size was associated with extra-pericardial fat volume, while appendix fat cell size was associated with BMI only. No predictors were associated with epicardial fat cell size in females at the univariable or multivariable levels. To conclude, no clinical measurements were useful surrogates of epicardial fat cell size in females, while BMI, age, and epicardial fat volume were independent, albeit weak, predictors in males only.
{"title":"Identifying sex differences in predictors of epicardial fat cell morphology.","authors":"Helen M M Waddell, Matthew K Moore, Morgan A Herbert-Olsen, Martin K Stiles, Rexson D Tse, Sean Coffey, Regis R Lamberts, Hamish M Aitken-Buck","doi":"10.1080/21623945.2022.2073854","DOIUrl":"https://doi.org/10.1080/21623945.2022.2073854","url":null,"abstract":"<p><p>Predictors of overall epicardial adipose tissue deposition have been found to vary between males and females. Whether similar sex differences exist in epicardial fat cell morphology is currently unknown. This study aimed to determine whether epicardial fat cell size is associated with different clinical measurements in males and females. Fat cell sizes were measured from epicardial, paracardial, and appendix adipose tissues of post-mortem cases (<i>N</i>= 118 total, 37 females). Epicardial, extra-pericardial, and visceral fat volumes were measured by computed tomography from a subset of cases (<i>N</i>= 70, 22 females). Correlation analyses and stepwise linear regression were performed to identify predictors of fat cell size in males and females. Median fat cell sizes in all depots did not differ between males and females. Body mass index (BMI) and age were independently predictive of epicardial, paracardial, and appendix fat cell sizes in males, but not in females. Epicardial and appendix fat cell sizes were associated with epicardial and visceral fat volumes, respectively, in males only. In females, paracardial fat cell size was associated with extra-pericardial fat volume, while appendix fat cell size was associated with BMI only. No predictors were associated with epicardial fat cell size in females at the univariable or multivariable levels. To conclude, no clinical measurements were useful surrogates of epicardial fat cell size in females, while BMI, age, and epicardial fat volume were independent, albeit weak, predictors in males only.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10248091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Obesity is associated with the infiltration of monocytes/macrophages into adipose tissue in which MCP-1 plays a crucial role. But the regulatory mechanism of MCP-1 expression in adipocytes is not well defined. Our results demonstrated that TNF-α induced abundant MCP-1 production in adipocytes, including 3T3-L1 pre- (≈ 9 to 18-fold), mature adipocytes (≈ 4 to 6-fold), and primary adipocytes(< 2-fold), among which 3T3-L1 pre-adipocytes showed the best reactiveness. Thus, 3T3-L1 pre-adipocytes were used for the most of following experiments. At the transcriptional level, TNF-α (20 ng/mL) also promoted the mRNA expression of MCP-1. It is well recognized that the engagement of TNF-α with its receptor can trigger both NF-κB and AP-1 signalling, which was also confirmed in our study (5-fold and 2-fold). Unexpectedly and counterintuitively, multiple NF-κB inhibitors with different mechanisms failed to suppress TNF-α-induced MCP-1 production, but rather the inhibitors for any one of MAPKs (JNK, ERK and p38) could do. This study, for the first time, reveals that MAPKs/AP-1 but not NF-κB signalling is responsible for MCP-1 production in TNF-α-activated adipocytes. These findings provide important insight into the role of AP-1 signalling in adipose tissue, and may lead to the development of therapeutical repositioning strategies in metaflammation.Abbreviations: AP-1, activator protein-1; CHX, cycloheximide; IR, insulin resistance; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; RT-qPCR, quantitative real-time PCR; T2DM, type 2 diabetes mellitus; TRE, triphorbol acetate-response element.
{"title":"MAPKs/AP-1, not NF-κB, is responsible for MCP-1 production in TNF-α-activated adipocytes.","authors":"Xiaoyu Zhang, Zhuangzhuang Liu, Wenjing Li, Yuan Kang, Zhenlu Xu, Ximeng Li, Yuan Gao, Yun Qi","doi":"10.1080/21623945.2022.2107786","DOIUrl":"https://doi.org/10.1080/21623945.2022.2107786","url":null,"abstract":"<p><p>Obesity is associated with the infiltration of monocytes/macrophages into adipose tissue in which MCP-1 plays a crucial role. But the regulatory mechanism of MCP-1 expression in adipocytes is not well defined. Our results demonstrated that TNF-α induced abundant MCP-1 production in adipocytes, including 3T3-L1 pre- (≈ 9 to 18-fold), mature adipocytes (≈ 4 to 6-fold), and primary adipocytes(< 2-fold), among which 3T3-L1 pre-adipocytes showed the best reactiveness. Thus, 3T3-L1 pre-adipocytes were used for the most of following experiments. At the transcriptional level, TNF-α (20 ng/mL) also promoted the mRNA expression of MCP-1. It is well recognized that the engagement of TNF-α with its receptor can trigger both NF-κB and AP-1 signalling, which was also confirmed in our study (5-fold and 2-fold). Unexpectedly and counterintuitively, multiple NF-κB inhibitors with different mechanisms failed to suppress TNF-α-induced MCP-1 production, but rather the inhibitors for any one of MAPKs (JNK, ERK and p38) could do. This study, for the first time, reveals that MAPKs/AP-1 but not NF-κB signalling is responsible for MCP-1 production in TNF-α-activated adipocytes. These findings provide important insight into the role of AP-1 signalling in adipose tissue, and may lead to the development of therapeutical repositioning strategies in metaflammation.<b>Abbreviations:</b> AP-1, activator protein-1; CHX, cycloheximide; IR, insulin resistance; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; RT-qPCR, quantitative real-time PCR; T2DM, type 2 diabetes mellitus; TRE, triphorbol acetate-response element.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40596214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.1080/21623945.2022.2154112
Clarissa Strieder-Barboza, Carmen G Flesher, Lynn M Geletka, Tad Eichler, Olukemi Akinleye, Alexander Ky, Anne P Ehlers, Carey N Lumeng, Robert W O'Rourke
Obesity-associated type 2 diabetes (DM) leads to adipose tissue dysfunction. Lumican is a proteoglycan implicated in obesity, insulin resistance (IR), and adipocyte dysfunction. Using human visceral adipose tissue (VAT) from subjects with and without DM, we studied lumican effects on adipocyte function. Lumican was increased in VAT and adipocytes in DM. Lumican knockdown in adipocytes decreased lipolysis and improved adipogenesis and insulin sensitivity in VAT adipocytes in DM, while treatment with human recombinant lumican increased lipolysis and impaired insulin-sensitivity in an ERK-dependent manner. We demonstrate that lumican impairs adipocyte metabolism, partially via ERK signalling, and is a potential target for developing adipose tissue-targeted therapeutics in DM.
{"title":"Lumican modulates adipocyte function in obesity-associated type 2 diabetes.","authors":"Clarissa Strieder-Barboza, Carmen G Flesher, Lynn M Geletka, Tad Eichler, Olukemi Akinleye, Alexander Ky, Anne P Ehlers, Carey N Lumeng, Robert W O'Rourke","doi":"10.1080/21623945.2022.2154112","DOIUrl":"10.1080/21623945.2022.2154112","url":null,"abstract":"<p><p>Obesity-associated type 2 diabetes (DM) leads to adipose tissue dysfunction. Lumican is a proteoglycan implicated in obesity, insulin resistance (IR), and adipocyte dysfunction. Using human visceral adipose tissue (VAT) from subjects with and without DM, we studied lumican effects on adipocyte function. Lumican was increased in VAT and adipocytes in DM. Lumican knockdown in adipocytes decreased lipolysis and improved adipogenesis and insulin sensitivity in VAT adipocytes in DM, while treatment with human recombinant lumican increased lipolysis and impaired insulin-sensitivity in an ERK-dependent manner. We demonstrate that lumican impairs adipocyte metabolism, partially via ERK signalling, and is a potential target for developing adipose tissue-targeted therapeutics in DM.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.1080/21623945.2021.2013415
Alyssa Thunen, Deirdre La Placa, Zhifang Zhang, John E Shively
Recent studies have identified long non-coding RNAs (lncRNAs) as potential regulators of adipogenesis. In this study, we have characterized a lncRNA, LIPE-AS1, that spans genes CEACAM1 to LIPE in man with conservation of genomic organization and tissue expression between mouse and man. Tissue-specific expression of isoforms of the murine lncRNA were found in liver and adipose tissue, one of which, designated mLas-V3, overlapped the Lipe gene encoding hormone-sensitive lipase in both mouse and man suggesting that it may have a functional role in adipose tissue. Knock down of expression of mLas-V3 using anti-sense oligos (ASOs) led to a significant decrease in the differentiation of the OP9 pre-adipocyte cell line through the down regulation of the major adipogenic transcription factors Pparg and Cebpa. Knock down of mLas-V3 induced apoptosis during the differentiation of OP9 cells as shown by expression of active caspase-3, a change in the localization of LIP/LAP isoforms of C/EBPβ, and expression of the cellular stress induced factors CHOP, p53, PUMA, and NOXA. We conclude that mLas-V3 may play a role in protecting against stress associated with adipogenesis, and its absence leads to apoptosis.
{"title":"Role of lncRNA LIPE-AS1 in adipogenesis.","authors":"Alyssa Thunen, Deirdre La Placa, Zhifang Zhang, John E Shively","doi":"10.1080/21623945.2021.2013415","DOIUrl":"https://doi.org/10.1080/21623945.2021.2013415","url":null,"abstract":"<p><p>Recent studies have identified long non-coding RNAs (lncRNAs) as potential regulators of adipogenesis. In this study, we have characterized a lncRNA, LIPE-AS1, that spans genes <i>CEACAM1</i> to <i>LIPE</i> in man with conservation of genomic organization and tissue expression between mouse and man. Tissue-specific expression of isoforms of the murine lncRNA were found in liver and adipose tissue, one of which, designated mLas-V3, overlapped the <i>Lipe</i> gene encoding hormone-sensitive lipase in both mouse and man suggesting that it may have a functional role in adipose tissue. Knock down of expression of mLas-V3 using anti-sense oligos (ASOs) led to a significant decrease in the differentiation of the OP9 pre-adipocyte cell line through the down regulation of the major adipogenic transcription factors <i>Pparg</i> and <i>Cebpa</i>. Knock down of mLas-V3 induced apoptosis during the differentiation of OP9 cells as shown by expression of active caspase-3, a change in the localization of LIP/LAP isoforms of C/EBPβ, and expression of the cellular stress induced factors CHOP, p53, PUMA, and NOXA. We conclude that mLas-V3 may play a role in protecting against stress associated with adipogenesis, and its absence leads to apoptosis.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39626821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Obesity is a complex medical condition that affects multiple organs in the body. However, the underlying mechanisms of obesity, as well as its treatment, are largely unexplored. The focus of this research was to use bioinformatics to discover possible treatment targets for obesity. To begin, the GSE133099 database was used to identify 364 differentially expressed genes (DEGs). Then, DEGs were subjected to tissue-specific analyses and enrichment analyses, followed by the creation of a protein-protein interaction (PPI) network and generation of a drug-gene interaction database to screen key genes and potential future drugs targeting obesity. Findings have illustrated that the tissue-specific expression of neurologic markers varied significantly (34.7%, 52/150). Among these genes, Lep, ApoE, Fyn, and FN1 were the key genes observed in the adipocyte samples from obese patients relative to the controls. Furthermore, nine potential therapeutic drugs (dasatinib, ocriplasmin, risperidone, gemfibrozil, ritonavir, fluvastatin, pravastatin, warfarin, atorvastatin) that target the key genes were also screened and selected. To conclude the key genes discovered (Lep, ApoE, Fyn, and FN1), as well as 9 candidate drugs, could be used as therapeutic targets in treating obesity.
{"title":"Bioinformatics analysis of candidate genes and potential therapeutic drugs targeting adipose tissue in obesity.","authors":"Yun Yu, Yu-Han Zhang, Liang Liu, Ling-Ling Yu, Jun-Pei Li, Jing-An Rao, Feng Hu, Ling-Juan Zhu, Hui-Hui Bao, Xiao-Shu Cheng","doi":"10.1080/21623945.2021.2013406","DOIUrl":"https://doi.org/10.1080/21623945.2021.2013406","url":null,"abstract":"<p><p>Obesity is a complex medical condition that affects multiple organs in the body. However, the underlying <i>mechanisms</i> of obesity, as well as its treatment, <i>are largely unexplored</i>. The focus of this research was to use bioinformatics to discover possible treatment targets for obesity. To begin, the GSE133099 database was used to identify 364 differentially expressed genes (DEGs). Then, DEGs were subjected to tissue-specific analyses and enrichment analyses, followed by the creation of a protein-protein interaction (PPI) network and generation of a drug-gene interaction database to screen key genes and potential future drugs targeting obesity. Findings have illustrated that the tissue-specific expression of neurologic markers varied significantly (34.7%, 52/150). Among these genes, Lep, ApoE, Fyn, and FN1 were the key genes observed in the adipocyte samples from obese patients relative to the controls. Furthermore, nine potential therapeutic drugs (dasatinib, ocriplasmin, risperidone, gemfibrozil, ritonavir, fluvastatin, pravastatin, warfarin, atorvastatin) that target the key genes were also screened and selected. To conclude the key genes discovered (Lep, ApoE, Fyn, and FN1), as well as 9 candidate drugs, could be used as therapeutic targets in treating obesity.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c4/ea/KADI_11_2013406.PMC8726706.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39770386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
White adipose tissue wasting plays a critical role in the development and progression of cancer cachexia. However, the mechanism behind the loss of adipose tissue remains ill-defined. In this study, we found that cancer cell-derived exosomes highly expressed miR-425-3p. Administration of cancer cell-derived exosomes significantly inhibited proliferation and differentiation of human preadipocytes-viscereal (HPA-v) cells. In mature adipocytes, cancer cell-derived exosomes activated cAMP/PKA signalling and lipophagy, leading to adipocyte lipolysis and browning of white adipocytes. These exosomes-induced alterations were almost abolished by endocytosis inhibitor cytochalasin D (CytoD) and antagomiR-425-3p, or reproduced by miR-425-3p mimics. In addition, bioinformatics analysis and luciferase reporter assay revealed that miR-425-3p directly targeted proliferation-related genes such as GATA2, IGFBP4, MMP15, differentiation-related gene CEBPA, and phosphodiesterase 4B gene (PDE4B). Depletion of PDE4B enhanced cAMP/PKA signalling and lipophagy, but had no effects on HPA-v proliferation and differentiation. Taken together, these results suggested that cancer cell-derived exosomal miR-425-3p inhibited preadipocyte proliferation and differentiation, increased adipocyte lipolysis, and promoted browning of white adipocytes, all of which might contribute to adipocyte atrophy and ultimately the loss of adipose tissue in cancer cachexia.Abbreviations: ADPN: adiponectin; aP2: adipocyte protein 2 or fatty acid binding protein 4 (FABP4); BCA: bicinchoninic acid assay; BFA: bafilomycin A1; BMI: body mass index; C/EBP: CCAAT/enhancer binding protein; CEBPA: CCAAT/enhancer-binding protein-alpha; C-Exo: cancer cell-derived exosomes; CNTL: control; CREB: cAMP-response element binding protein; CytoD: cytochalasin D; ECL: chemiluminescence; GATA2: GATA Binding Protein 2; HFD: high fat diet; HSL: hormone-sensitive lipase; IGFBP4: insulin like growth factor binding protein 4; IRS-1: insulin receptor substrate-1; ISO: isoproterenol hydrochloride; KD: knockdown; KO: knock out; LC3: microtubule-associated protein 1A/1B-light chain 3; LMF: lipid mobilizing factor; LPL: lipoprotein lipase; MMP15: matrix metallopeptidase 15; Mir-Inh-C-Exo: cancer cell-derived exosomes with miR-425-3p inhibition; mTOR: mammalian target of rapamycin; Mut: mutant; N-Exo: normal cell-derived exosomes; NSCLC: non-small cell lung cancer; PBS, phosphate buffered saline; PGC-1: peroxisome proliferator-activated receptor-gamma coactivator-1; PDEs: phosphodiesterases; PKI: PKA inhibitor; PKA: cAMP-dependent protein kinase; PLIN1: Perilipin 1; PTHRP: parathyroid hormone-related protein; PVDF: polyvinylidene difluoride; shRNA: short hairpin RNA; UCP1: uncoupling protein 1; WT: wild type.
{"title":"Cancer cell-derived exosomal miR-425-3p induces white adipocyte atrophy.","authors":"Anwen Liu, Wenxia Pan, Shutong Zhuang, Yuanzhi Tang, Haitao Zhang","doi":"10.1080/21623945.2022.2108558","DOIUrl":"https://doi.org/10.1080/21623945.2022.2108558","url":null,"abstract":"<p><p>White adipose tissue wasting plays a critical role in the development and progression of cancer cachexia. However, the mechanism behind the loss of adipose tissue remains ill-defined. In this study, we found that cancer cell-derived exosomes highly expressed miR-425-3p. Administration of cancer cell-derived exosomes significantly inhibited proliferation and differentiation of human preadipocytes-viscereal (HPA-v) cells. In mature adipocytes, cancer cell-derived exosomes activated cAMP/PKA signalling and lipophagy, leading to adipocyte lipolysis and browning of white adipocytes. These exosomes-induced alterations were almost abolished by endocytosis inhibitor cytochalasin D (CytoD) and antagomiR-425-3p, or reproduced by miR-425-3p mimics. In addition, bioinformatics analysis and luciferase reporter assay revealed that miR-425-3p directly targeted proliferation-related genes such as <i>GATA2, IGFBP4, MMP15</i>, differentiation-related gene <i>CEBPA</i>, and phosphodiesterase 4B gene (<i>PDE4B</i>). Depletion of PDE4B enhanced cAMP/PKA signalling and lipophagy, but had no effects on HPA-v proliferation and differentiation. Taken together, these results suggested that cancer cell-derived exosomal miR-425-3p inhibited preadipocyte proliferation and differentiation, increased adipocyte lipolysis, and promoted browning of white adipocytes, all of which might contribute to adipocyte atrophy and ultimately the loss of adipose tissue in cancer cachexia.<b>Abbreviations:</b> ADPN: adiponectin; aP2: adipocyte protein 2 or fatty acid binding protein 4 (FABP4); BCA: bicinchoninic acid assay; BFA: bafilomycin A1; BMI: body mass index; C/EBP: CCAAT/enhancer binding protein; CEBPA: CCAAT/enhancer-binding protein-alpha; C-Exo: cancer cell-derived exosomes; CNTL: control; CREB: cAMP-response element binding protein; CytoD: cytochalasin D; ECL: chemiluminescence; GATA2: GATA Binding Protein 2; HFD: high fat diet; HSL: hormone-sensitive lipase; IGFBP4: insulin like growth factor binding protein 4; IRS-1: insulin receptor substrate-1; ISO: isoproterenol hydrochloride; KD: knockdown; KO: knock out; LC3: microtubule-associated protein 1A/1B-light chain 3; LMF: lipid mobilizing factor; LPL: lipoprotein lipase; MMP15: matrix metallopeptidase 15; Mir-Inh-C-Exo: cancer cell-derived exosomes with miR-425-3p inhibition; mTOR: mammalian target of rapamycin; Mut: mutant; N-Exo: normal cell-derived exosomes; NSCLC: non-small cell lung cancer; PBS, phosphate buffered saline; PGC-1: peroxisome proliferator-activated receptor-gamma coactivator-1; PDEs: phosphodiesterases; PKI: PKA inhibitor; PKA: cAMP-dependent protein kinase; PLIN1: Perilipin 1; PTHRP: parathyroid hormone-related protein; PVDF: polyvinylidene difluoride; shRNA: short hairpin RNA; UCP1: uncoupling protein 1; WT: wild type.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40611171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.1080/21623945.2022.2091206
Fan Hu, Chang Li, Yafen Ye, Xuhong Lu, Miriayi Alimujiang, Ningning Bai, Jingjing Sun, Xiaojing Ma, Xiaohua Li, Ying Yang
PARP12 is a member of poly-ADP-ribosyl polymerase (PARPs), which has been characterized for its antiviral function. Yet its physiological implication in adipocytes remains unknown. Here, we report a central function of PARP12 in thermogenic adipocytes. We show that PARP12 is highly expressed in brown adipose tissue and is mainly localized to the mitochondria. Knockdown of PARP12 in vitro reduced UCP1 expression. In parallel, the deficiency of PARP12 reduced mitochondrial respiration in adipocytes, while overexpression of PARP12 reversed these effects.
{"title":"PARP12 is required for mitochondrial function maintenance in thermogenic adipocytes.","authors":"Fan Hu, Chang Li, Yafen Ye, Xuhong Lu, Miriayi Alimujiang, Ningning Bai, Jingjing Sun, Xiaojing Ma, Xiaohua Li, Ying Yang","doi":"10.1080/21623945.2022.2091206","DOIUrl":"https://doi.org/10.1080/21623945.2022.2091206","url":null,"abstract":"<p><p>PARP12 is a member of poly-ADP-ribosyl polymerase (PARPs), which has been characterized for its antiviral function. Yet its physiological implication in adipocytes remains unknown. Here, we report a central function of PARP12 in thermogenic adipocytes. We show that PARP12 is highly expressed in brown adipose tissue and is mainly localized to the mitochondria. Knockdown of PARP12 in vitro reduced UCP1 expression. In parallel, the deficiency of PARP12 reduced mitochondrial respiration in adipocytes, while overexpression of PARP12 reversed these effects.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40675288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.1080/21623945.2022.2148886
Elena Kempf, Kathrin Landgraf, Tim Vogel, Ulrike Spielau, Robert Stein, Matthias Raschpichler, Jürgen Kratzsch, Wieland Kiess, Juraj Stanik, Antje Körner
Components of the growth hormone (GH) axis, such as insulin-like growth factor-1 (IGF-1), IGF-1 binding protein-3 (IGFBP-3), GH receptor (GHR) and GH-binding protein (GHBP), regulate growth and metabolic pathways. Here, we asked if serum levels of these factors are altered with overweight/obesity and if this is related to adipose tissue (AT) expression and/or increased fat mass. Furthermore, we hypothesized that expression of GHR, IGF-1 and IGFBP-3 is associated with AT function. Serum GHBP levels were increased in children with overweight/obesity throughout childhood, while for IGF-1 levels and the IGF-1/IGFBP-3 molar ratio obesity-related elevations were detectable until early puberty. Circulating levels did not correlate with AT expression of these factors, which was decreased with overweight/obesity. Independent from obesity, expression of GHR, IGF-1 and IGFBP-3 was related to AT dysfunction,and increased insulin levels. Serum GHBP was associated with liver fat percentage and transaminase levels. We conclude that obesity-related elevations in serum GHBP and IGF-1 are unlikely to be caused by increased AT mass and elevations in GHBP are more closely related to liver status in children. The diminished AT expression of these factors with childhood obesity may contribute to early AT dysfunction and a deterioration of the metabolic state.
{"title":"Associations of <i>GHR, IGF-1</i> and <i>IGFBP-3</i> expression in adipose tissue cells with obesity-related alterations in corresponding circulating levels and adipose tissue function in children.","authors":"Elena Kempf, Kathrin Landgraf, Tim Vogel, Ulrike Spielau, Robert Stein, Matthias Raschpichler, Jürgen Kratzsch, Wieland Kiess, Juraj Stanik, Antje Körner","doi":"10.1080/21623945.2022.2148886","DOIUrl":"https://doi.org/10.1080/21623945.2022.2148886","url":null,"abstract":"<p><p>Components of the growth hormone (GH) axis, such as insulin-like growth factor-1 (IGF-1), IGF-1 binding protein-3 (IGFBP-3), GH receptor (GHR) and GH-binding protein (GHBP), regulate growth and metabolic pathways. Here, we asked if serum levels of these factors are altered with overweight/obesity and if this is related to adipose tissue (AT) expression and/or increased fat mass. Furthermore, we hypothesized that expression of <i>GHR, IGF-1</i> and <i>IGFBP-3</i> is associated with AT function. Serum GHBP levels were increased in children with overweight/obesity throughout childhood, while for IGF-1 levels and the IGF-1/IGFBP-3 molar ratio obesity-related elevations were detectable until early puberty. Circulating levels did not correlate with AT expression of these factors, which was decreased with overweight/obesity. Independent from obesity, expression of <i>GHR, IGF-1</i> and <i>IGFBP-3</i> was related to AT dysfunction,and increased insulin levels. Serum GHBP was associated with liver fat percentage and transaminase levels. We conclude that obesity-related elevations in serum GHBP and IGF-1 are unlikely to be caused by increased AT mass and elevations in GHBP are more closely related to liver status in children. The diminished AT expression of these factors with childhood obesity may contribute to early AT dysfunction and a deterioration of the metabolic state.</p>","PeriodicalId":7226,"journal":{"name":"Adipocyte","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9683049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10618079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}