SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways
<p>The NAD<sup>+</sup>-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD<sup>+</sup> boosters alleviate metabolic complications. We previously repo...
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2021
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| _version_ | 1864513555764609024 |
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| author | Yasser Majeed (9417974) |
| author2 | Najeeb Halabi (102754) Aisha Y. Madani (14152911) Rudolf Engelke (1754893) Aditya M. Bhagwat (14152806) Houari Abdesselem (14152914) Maha V. Agha (7956170) Muneera Vakayil (12037693) Raphael Courjaret (9592368) Neha Goswami (9500432) Hisham Ben Hamidane (2048128) Mohamed A. Elrayess (7956179) Arash Rafii (102768) Johannes Graumann (1297758) Frank Schmidt (207186) Nayef A. Mazloum (7355087) |
| author2_role | author author author author author author author author author author author author author author author |
| author_facet | Yasser Majeed (9417974) Najeeb Halabi (102754) Aisha Y. Madani (14152911) Rudolf Engelke (1754893) Aditya M. Bhagwat (14152806) Houari Abdesselem (14152914) Maha V. Agha (7956170) Muneera Vakayil (12037693) Raphael Courjaret (9592368) Neha Goswami (9500432) Hisham Ben Hamidane (2048128) Mohamed A. Elrayess (7956179) Arash Rafii (102768) Johannes Graumann (1297758) Frank Schmidt (207186) Nayef A. Mazloum (7355087) |
| author_role | author |
| dc.creator.none.fl_str_mv | Yasser Majeed (9417974) Najeeb Halabi (102754) Aisha Y. Madani (14152911) Rudolf Engelke (1754893) Aditya M. Bhagwat (14152806) Houari Abdesselem (14152914) Maha V. Agha (7956170) Muneera Vakayil (12037693) Raphael Courjaret (9592368) Neha Goswami (9500432) Hisham Ben Hamidane (2048128) Mohamed A. Elrayess (7956179) Arash Rafii (102768) Johannes Graumann (1297758) Frank Schmidt (207186) Nayef A. Mazloum (7355087) |
| dc.date.none.fl_str_mv | 2021-04-14T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-021-87759-x |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/SIRT1_promotes_lipid_metabolism_and_mitochondrial_biogenesis_in_adipocytes_and_coordinates_adipogenesis_by_targeting_key_enzymatic_pathways/21598227 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Endocrine system and metabolic diseases Endocrinology Metabolism |
| dc.title.none.fl_str_mv | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>The NAD<sup>+</sup>-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD<sup>+</sup> boosters alleviate metabolic complications. We previously reported that SIRT1-depletion in 3T3-L1 preadipocytes led to C-Myc activation, adipocyte hyperplasia, and dysregulated adipocyte metabolism. Here, we characterized SIRT1-depleted adipocytes by quantitative mass spectrometry-based proteomics, gene-expression and biochemical analyses, and mitochondrial studies. We found that SIRT1 promoted mitochondrial biogenesis and respiration in adipocytes and expression of molecules like leptin, adiponectin, matrix metalloproteinases, lipocalin 2, and thyroid responsive protein was SIRT1-dependent. Independent validation of the proteomics dataset uncovered SIRT1-dependence of SREBF1c and PPARα signaling in adipocytes. SIRT1 promoted nicotinamide mononucleotide acetyltransferase 2 (NMNAT2) expression during 3T3-L1 differentiation and constitutively repressed NMNAT1 and 3 levels. Supplementing preadipocytes with the NAD+ booster nicotinamide mononucleotide (NMN) during differentiation increased expression levels of leptin, SIRT1, and PGC-1α and its transcriptional targets, and reduced levels of pro-fibrotic collagens (Col6A1 and Col6A3) in a SIRT1-dependent manner. Investigating the metabolic impact of the functional interaction of SIRT1 with SREBF1c and PPARα and insights into how NAD<sup>+</sup> metabolism modulates adipocyte function could potentially lead to new avenues in developing therapeutics for obesity complications.</p> <h2>Other Information</h2> <p>Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br> See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41598-021-87759-x" target="_blank">http://dx.doi.org/10.1038/s41598-021-87759-x</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_41e0ebea4a7fe607ded6dc915dfd994a |
| identifier_str_mv | 10.1038/s41598-021-87759-x |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21598227 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathwaysYasser Majeed (9417974)Najeeb Halabi (102754)Aisha Y. Madani (14152911)Rudolf Engelke (1754893)Aditya M. Bhagwat (14152806)Houari Abdesselem (14152914)Maha V. Agha (7956170)Muneera Vakayil (12037693)Raphael Courjaret (9592368)Neha Goswami (9500432)Hisham Ben Hamidane (2048128)Mohamed A. Elrayess (7956179)Arash Rafii (102768)Johannes Graumann (1297758)Frank Schmidt (207186)Nayef A. Mazloum (7355087)Biomedical and clinical sciencesClinical sciencesMedical biochemistry and metabolomicsEndocrine system and metabolic diseasesEndocrinologyMetabolism<p>The NAD<sup>+</sup>-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD<sup>+</sup> boosters alleviate metabolic complications. We previously reported that SIRT1-depletion in 3T3-L1 preadipocytes led to C-Myc activation, adipocyte hyperplasia, and dysregulated adipocyte metabolism. Here, we characterized SIRT1-depleted adipocytes by quantitative mass spectrometry-based proteomics, gene-expression and biochemical analyses, and mitochondrial studies. We found that SIRT1 promoted mitochondrial biogenesis and respiration in adipocytes and expression of molecules like leptin, adiponectin, matrix metalloproteinases, lipocalin 2, and thyroid responsive protein was SIRT1-dependent. Independent validation of the proteomics dataset uncovered SIRT1-dependence of SREBF1c and PPARα signaling in adipocytes. SIRT1 promoted nicotinamide mononucleotide acetyltransferase 2 (NMNAT2) expression during 3T3-L1 differentiation and constitutively repressed NMNAT1 and 3 levels. Supplementing preadipocytes with the NAD+ booster nicotinamide mononucleotide (NMN) during differentiation increased expression levels of leptin, SIRT1, and PGC-1α and its transcriptional targets, and reduced levels of pro-fibrotic collagens (Col6A1 and Col6A3) in a SIRT1-dependent manner. Investigating the metabolic impact of the functional interaction of SIRT1 with SREBF1c and PPARα and insights into how NAD<sup>+</sup> metabolism modulates adipocyte function could potentially lead to new avenues in developing therapeutics for obesity complications.</p> <h2>Other Information</h2> <p>Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br> See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41598-021-87759-x" target="_blank">http://dx.doi.org/10.1038/s41598-021-87759-x</a></p>2021-04-14T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-021-87759-xhttps://figshare.com/articles/journal_contribution/SIRT1_promotes_lipid_metabolism_and_mitochondrial_biogenesis_in_adipocytes_and_coordinates_adipogenesis_by_targeting_key_enzymatic_pathways/21598227CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215982272021-04-14T06:00:00Z |
| spellingShingle | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways Yasser Majeed (9417974) Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Endocrine system and metabolic diseases Endocrinology Metabolism |
| status_str | publishedVersion |
| title | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| title_full | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| title_fullStr | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| title_full_unstemmed | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| title_short | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| title_sort | SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| topic | Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Endocrine system and metabolic diseases Endocrinology Metabolism |