SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways
Abstract The NAD+-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD+ boosters alleviate metabolic complications. We previously reported that SIRT1-depletion in 3T3-L1 preadipocy...
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Nature Portfolio
2021
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oai:doaj.org-article:089c9cec17554b53999e1600d089c0342021-12-02T14:30:39ZSIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways10.1038/s41598-021-87759-x2045-2322https://doaj.org/article/089c9cec17554b53999e1600d089c0342021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87759-xhttps://doaj.org/toc/2045-2322Abstract The NAD+-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD+ 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+ metabolism modulates adipocyte function could potentially lead to new avenues in developing therapeutics for obesity complications.Yasser MajeedNajeeb HalabiAisha Y. MadaniRudolf EngelkeAditya M. BhagwatHouari AbdesselemMaha V. AghaMuneera VakayilRaphael CourjaretNeha GoswamiHisham Ben HamidaneMohamed A. ElrayessArash RafiiJohannes GraumannFrank SchmidtNayef A. MazloumNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
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Medicine R Science Q |
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Medicine R Science Q Yasser Majeed Najeeb Halabi Aisha Y. Madani Rudolf Engelke Aditya M. Bhagwat Houari Abdesselem Maha V. Agha Muneera Vakayil Raphael Courjaret Neha Goswami Hisham Ben Hamidane Mohamed A. Elrayess Arash Rafii Johannes Graumann Frank Schmidt Nayef A. Mazloum SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| description |
Abstract The NAD+-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD+ 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+ metabolism modulates adipocyte function could potentially lead to new avenues in developing therapeutics for obesity complications. |
| format |
article |
| author |
Yasser Majeed Najeeb Halabi Aisha Y. Madani Rudolf Engelke Aditya M. Bhagwat Houari Abdesselem Maha V. Agha Muneera Vakayil Raphael Courjaret Neha Goswami Hisham Ben Hamidane Mohamed A. Elrayess Arash Rafii Johannes Graumann Frank Schmidt Nayef A. Mazloum |
| author_facet |
Yasser Majeed Najeeb Halabi Aisha Y. Madani Rudolf Engelke Aditya M. Bhagwat Houari Abdesselem Maha V. Agha Muneera Vakayil Raphael Courjaret Neha Goswami Hisham Ben Hamidane Mohamed A. Elrayess Arash Rafii Johannes Graumann Frank Schmidt Nayef A. Mazloum |
| author_sort |
Yasser Majeed |
| title |
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_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_sort |
sirt1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/089c9cec17554b53999e1600d089c034 |
| work_keys_str_mv |
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1718391172762697728 |