Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling
Objective: Obesity due to overnutrition causes adipose tissue dysfunction, which is a critical pathological step on the road to type 2 diabetes (T2D) and other metabolic disorders. In this study, we conducted an unbiased investigation into the fundamental molecular mechanisms by which adipocytes tra...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820301605 |
| _version_ | 1818955948372262912 |
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| author | Hyun Cheol Roh Manju Kumari Solaema Taleb Danielle Tenen Christopher Jacobs Anna Lyubetskaya Linus T.-Y. Tsai Evan D. Rosen |
| author_facet | Hyun Cheol Roh Manju Kumari Solaema Taleb Danielle Tenen Christopher Jacobs Anna Lyubetskaya Linus T.-Y. Tsai Evan D. Rosen |
| author_sort | Hyun Cheol Roh |
| collection | DOAJ |
| description | Objective: Obesity due to overnutrition causes adipose tissue dysfunction, which is a critical pathological step on the road to type 2 diabetes (T2D) and other metabolic disorders. In this study, we conducted an unbiased investigation into the fundamental molecular mechanisms by which adipocytes transition to an unhealthy state during obesity. Methods: We used nuclear tagging and translating ribosome affinity purification (NuTRAP) reporter mice crossed with Adipoq-Cre mice to determine adipocyte-specific 1) transcriptional profiles (RNA-seq), 2) promoter and enhancer activity (H3K27ac ChIP-seq), 3) and PPARγ cistrome (ChIP-seq) profiles in mice fed chow or a high-fat diet (HFD) for 10 weeks. We also assessed the impact of the PPARγ agonist rosiglitazone (Rosi) on gene expression and cellular state of adipocytes from the HFD-fed mice. We integrated these data to determine the transcription factors underlying adipocyte responses to HFD and conducted functional studies using shRNA-mediated loss-of-function approaches in 3T3-L1 adipocytes. Results: Adipocytes from the HFD-fed mice exhibited reduced expression of adipocyte markers and metabolic genes and enhanced expression of myofibroblast marker genes involved in cytoskeletal organization, accompanied by the formation of actin filament structures within the cell. PPARγ binding was globally reduced in adipocytes after HFD feeding, and Rosi restored the molecular and cellular phenotypes of adipocytes associated with HFD feeding. We identified the TGFβ1 effector protein SMAD to be enriched at HFD-induced promoters and enhancers and associated with myofibroblast signature genes. TGFβ1 treatment of mature 3T3-L1 adipocytes induced gene expression and cellular changes similar to those seen after HFD in vivo, and knockdown of Smad3 blunted the effects of TGFβ1. Conclusions: Our data demonstrate that adipocytes fail to maintain cellular identity after HFD feeding, acquiring characteristics of a myofibroblast-like cell type through reduced PPARγ activity and elevated TGFβ-SMAD signaling. This cellular identity crisis may be a fundamental mechanism that drives functional decline of adipose tissues during obesity. |
| first_indexed | 2024-12-20T10:46:10Z |
| format | Article |
| id | doaj.art-bd566c0b1b1f41fea866ef6258042b4a |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-20T10:46:10Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-bd566c0b1b1f41fea866ef6258042b4a2022-12-21T19:43:24ZengElsevierMolecular Metabolism2212-87782020-12-0142101086Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signalingHyun Cheol Roh0Manju Kumari1Solaema Taleb2Danielle Tenen3Christopher Jacobs4Anna Lyubetskaya5Linus T.-Y. Tsai6Evan D. Rosen7Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA; Corresponding author. Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.Division of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USADivision of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USADivision of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USADivision of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USADivision of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USADivision of Endocrinology, Diabetes and Obesity, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA; Broad Institute, Cambridge, MA, 02142, USA; Corresponding author. Broad Institute, Cambridge, MA, 02142, USA.Objective: Obesity due to overnutrition causes adipose tissue dysfunction, which is a critical pathological step on the road to type 2 diabetes (T2D) and other metabolic disorders. In this study, we conducted an unbiased investigation into the fundamental molecular mechanisms by which adipocytes transition to an unhealthy state during obesity. Methods: We used nuclear tagging and translating ribosome affinity purification (NuTRAP) reporter mice crossed with Adipoq-Cre mice to determine adipocyte-specific 1) transcriptional profiles (RNA-seq), 2) promoter and enhancer activity (H3K27ac ChIP-seq), 3) and PPARγ cistrome (ChIP-seq) profiles in mice fed chow or a high-fat diet (HFD) for 10 weeks. We also assessed the impact of the PPARγ agonist rosiglitazone (Rosi) on gene expression and cellular state of adipocytes from the HFD-fed mice. We integrated these data to determine the transcription factors underlying adipocyte responses to HFD and conducted functional studies using shRNA-mediated loss-of-function approaches in 3T3-L1 adipocytes. Results: Adipocytes from the HFD-fed mice exhibited reduced expression of adipocyte markers and metabolic genes and enhanced expression of myofibroblast marker genes involved in cytoskeletal organization, accompanied by the formation of actin filament structures within the cell. PPARγ binding was globally reduced in adipocytes after HFD feeding, and Rosi restored the molecular and cellular phenotypes of adipocytes associated with HFD feeding. We identified the TGFβ1 effector protein SMAD to be enriched at HFD-induced promoters and enhancers and associated with myofibroblast signature genes. TGFβ1 treatment of mature 3T3-L1 adipocytes induced gene expression and cellular changes similar to those seen after HFD in vivo, and knockdown of Smad3 blunted the effects of TGFβ1. Conclusions: Our data demonstrate that adipocytes fail to maintain cellular identity after HFD feeding, acquiring characteristics of a myofibroblast-like cell type through reduced PPARγ activity and elevated TGFβ-SMAD signaling. This cellular identity crisis may be a fundamental mechanism that drives functional decline of adipose tissues during obesity.http://www.sciencedirect.com/science/article/pii/S2212877820301605Adipose tissueObesityCellular identityNuTRAPPPARγTGFβ-SMAD |
| spellingShingle | Hyun Cheol Roh Manju Kumari Solaema Taleb Danielle Tenen Christopher Jacobs Anna Lyubetskaya Linus T.-Y. Tsai Evan D. Rosen Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling Molecular Metabolism Adipose tissue Obesity Cellular identity NuTRAP PPARγ TGFβ-SMAD |
| title | Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling |
| title_full | Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling |
| title_fullStr | Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling |
| title_full_unstemmed | Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling |
| title_short | Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling |
| title_sort | adipocytes fail to maintain cellular identity during obesity due to reduced pparγ activity and elevated tgfβ smad signaling |
| topic | Adipose tissue Obesity Cellular identity NuTRAP PPARγ TGFβ-SMAD |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820301605 |
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