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 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.

Neochlorogenic Acid Attenuates Hepatic Lipid Accumulation and Inflammation via Regulating miR-34a In Vitro

“…AMPK activation inhibits the expression of acetyl CoA carboxylase and FAS by downregulating SREBPs, thus reducing the synthesis of fatty acids, cholesterols, and triglycerides and promoting fatty acid uptake and β-oxidation [ 10 ]. Furthermore, SIRT1, a nicotinamide adenine dinucleotide-dependent deacetylase, can induce mitochondrial biogenesis and suppress the gene transcription involved in adipogenesis [ 43 ]. SIRT1 has been observed to be inhibited by miR-34a, and it regulates the activity of AMPK [ 44 ].…”

NAFLD: Mechanisms, Treatments, and Biomarkers

“…SIRT1 is found in the nucleus and shuttles between the nucleus and cytoplasm under physiological and pathological conditions [ 206 , 207 ]. SIRT1 regulates, via deacetylation of transcription factors and proteins, multiple metabolic pathways in the liver, including FA synthesis and oxidation, oxidative phosphorylation, inflammation, mitochondrial biogenesis, and autophagy [ 202 , 206 , 208 , 209 ] ( Figure 2 ). The involvement of SIRTs in NAFLD has been shown in both human and animal models of NAFLD.…”

Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients – a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown

“…Hence, an effective treatment against lipodystrophy could normalize the level of these two adipokines and could additionally lower the risk of steatosis. Recent studies indicate that the reduction of the serum adiponectin and leptin levels could be a consequence of SIRT1-depleted adipocytes found during lipodistrophy ( 215 , 216 ). SIRT1, a member of the enzyme family of sirtuins, modulates the cellular metabolism, as well as HIV transcription ( 217 ).…”