SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways
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.
Other Information
Published in: Scientific Reports
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: http://dx.doi.org/10.1038/s41598-021-87759-x
Funding
Open access funding provided by the Qatar National Library.
Qatar National Research Fund (GSRA4-1-0330-17010), PhD-Molecular Mechanisms of Cellular Senescence.
Qatar National Research Fund (NPRP8-059-1-009), Determining the Function of SIRT1 in Preadipocyte Proliferation and Differentiation.
History
Language
- English
Publisher
Springer NaturePublication Year
- 2021
License statement
This Item is licensed under the Creative Commons Attribution 4.0 International License.Institution affiliated with
- Weill Cornell Medicine - Qatar
- Hamad Bin Khalifa University
- College of Health and Life Sciences - HBKU
- Qatar Biomedical Research Institute - HBKU
- Neurological Disorders Research Center - QBRI
- Hamad Medical Corporation
- Interim Translational Research Institute - HMC