Sirt1 In Adipose Tissue Research Articles

Sargassum thunbergii Extract Attenuates High-Fat Diet-Induced Obesity in Mice by Modulating AMPK Activation and the Gut Microbiota.

Sargassum thunbergii (Mertens ex Roth) Kuntze (ST) is a brown alga rich in indole-2-carboxaldehyde. This study aimed to investigate the anti-obesity effects of ethanol extract from ST in in vitro and in vivo models. In 3T3-L1 cells, ST extract significantly inhibited lipid accumulation in mature adipocytes while lowering adipogenic genes (C/epba and Pparg) and enhancing metabolic sensors (Ampk, Sirt1), thermogenic genes (Pgc-1a, Ucp1), and proteins (p-AMPK/AMPK and UCP1). During animal investigation, mice were administered a chow diet, a high-fat diet (HF), or an HF diet supplemented with ST extract (at dosages of 150 and 300 mg/kg bw per day) for 8 weeks (n = 10/group). ST extract administration decreased weight gain, white adipose tissue weight, LDL-cholesterol, and serum leptin levels while improving glucose intolerance. In addition, ST extract increased the expression of Ampk and Sirt1 in adipose tissue and in the liver, as well as p-AMPK/AMPK ratio in the liver, compared to HF-fed mice. The abundance of Bacteroides vulgatus and Faecalibacterium prausnitzii in the feces increased in response to ST extract administration, although levels of Romboutsia ilealis decreased compared with those in HF-fed mice. ST extract could prevent obesity in HF-fed mice via the modulation of AMPK activation and gut microbiota composition.

Clusterin is involved in mediating the metabolic function of adipose SIRT1

SummarySIRT1 is a metabolic sensor regulating energy homeostasis. The present study revealed that mice with selective overexpression of human SIRT1 in adipose tissue (Adipo-SIRT1) were protected from high-fat diet (HFD)-induced metabolic abnormalities. Adipose SIRT1 was enriched at mitochondria-ER contacts (MERCs) to trigger mitohormesis and unfolded protein response (UPRmt), in turn preventing ER stress. As a downstream target of UPRmt, clusterin was significantly upregulated and acted together with SIRT1 to regulate the protein and lipid compositions at MERCs of adipose tissue. In mice lacking clusterin, HFD-induced metabolic abnormalities were significantly enhanced and could not be prevented by overexpression of SIRT1 in adipose tissue. Treatment with ER stress inhibitors restored adipose SIRT1-mediated beneficial effects on systemic energy metabolism. In summary, adipose SIRT1 facilitated the dynamic interactions and communications between mitochondria and ER, via MERCs, in turn triggering a mild mitochondrial stress to instigate the defense responses against dietary obesity-induced metabolic dysfunctions.

Anti‐contractile activity of SIRT1 in the perivascular adipose tissue

Background ˗ Perivascular adipose tissue (PVAT) reduces the contraction of blood vessel at least in part by secreting transferable relaxing factors. Nevertheless, the molecular mechanisms underlying PVAT-mediated anti-contractile activity remain uncharacterized. The present study examined the role of SIRT1, a longevity regulator, in modulating the anti-contractile effects of PVAT. Methods and Results ˗ Mesenteric arteries with or without the attached PVAT were isolated from wild type animals (WT), or mice with selective overexpression of human SIRT1 in adipose tissues (Adipo-SIRT1). Wire myography was performed to examine phenylephrine-induced arterial contractions. PVAT derived from Adipo-SIRT1 exhibited dose- and time-dependent anti-contractile activity, which was not affected by feeding the animals with high fat diet. Molecular analyses revealed that overexpression of SIRT1 decreased the expression of Triadin, an important component of the calcium-releasing ryanodine receptor (RyR) channels. Treatment with dantrolene sodium, an inhibitor of RyR, increased the anti-contractile activity of PVAT derived from WT. Mechanistically, SIRT1-triggered mitochondrial hormesis via modulating the calcium flux from endoplasmic reticulum. The increased production of mitochondrial reactive oxygen species (mtROS) was critically involved in SIRT1-mediated anti-contractile activity of PVAT. The beneficial function of SIRT1 in PVAT was abolished in transgenic mice with selective overexpression of Triadin in adipose tissues (Adipo-TRDN). Conclusions ˗Increased SIRT1 expression in PVAT promotes vascular anti-contraction at least partly through down regulation of Triadin-mediated calcium signaling.

SUN-603 Electronic Cigarette Exposure Induces Pro-Inflammatory Changes in Adipose Tissue in Apolipoprotein E (APOE) Knockout Mice

Electronic nicotine delivery systems or electronic cigarettes (e-cigarettes) are becoming exceptionally popular in the world as an alternative to conventional nicotine cigarettes, both in smokers and people who have never smoked. Nicotine can induce lipolysis in adipose tissue, leading to increased serum free fatty acids (FFA). Increased levels of FFA are one of the key elements in inducing a pro-inflammatory response and lead to ectopic lipid accumulation, lipotoxicity, mitochondrial dysfunction and metabolic disease. Our laboratory has shown that chronic e-cigarette exposure induces cardiac dysfunction, atherosclerosis and hepatic steatosis in the ApoE knockout (KO) model associated with increased levels of serum FFA. In this study, we investigated the role of adipose tissue in the metabolic changes associated with e-cigarette exposure. ApoE KO mice were exposed to saline, e-cigarette without nicotine [e-cigarette (0%)] and e-cigarette with 2.4% nicotine [e-cigarette (2.4%)] aerosol for 12 weeks. Western blot analyses from adipose tissue showed that mice treated with e-cigarette (2.4%) had decrease levels of SIRT1 when compared to mice treated with saline or e-cigarette (0%). Transcriptomic analysis of the differentially expressed genes shows a differential transcriptional response to e-cigarette (2.4%) in adipose tissue in comparison with e-cigarette (0%) or saline. The RNA-seq examination using ingenuity pathway analysis (IPA) software, revealed dysregulation of fibrosis, agranulocyte and granulocyte adhesion and diapedesis pathways in e-cigarette (2.4%) -exposed adipose tissue. Overall, we found an inflammatory phenotype associated with decreased levels of SIRT1 in adipose tissue of mice treated with e-cigarette (2.4%). Understanding the consequences of e-cigarette use on metabolic disease is directly relevant to the development of policies related to e-cigarette use.

High-Fat Diet Triggers Inflammation-Induced Cleavage of SIRT1 in Adipose Tissue To Promote Metabolic Dysfunction

Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from inflammation and obesity under normal feeding conditions, and to forestall the progression to metabolic dysfunction under dietary stress and aging. Genetic ablation of SIRT1 in adipose tissue leads to gene expression changes that highly overlap with changes induced by high-fat diet in wild-type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high-fat diet induces the cleavage of SIRT1 protein in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction.

Food restriction improves glucose and lipid metabolism through Sirt1 expression: A study using a new rat model with obesity and severe hypertension

Aims To determine the effects of food restriction (FR) on the expression of Sirt1 and its down-stream factors related to lipid and glucose metabolism in obese and hypertensive rats (SHRSP/IDmcr- fa), as a model of human metabolic syndrome. Main methods Male, 10-week-old SHRSP/IDmcr- fa rats were treated with 85% FR for 2 weeks. Metabolic parameters, serum adipocytokines and distribution of serum adiponectin multimers were investigated. Sirt1 expression was determined in epididymal adipose tissue, liver and skeletal muscle. We also determined the expression of PPARα, γ and other adipocyte-related genes in epididymal adipose tissue, and glucose transporters (GLUT2 and GLUT4) in the liver and skeletal muscle. Key findings FR improved the general conditions as well as blood chemistry of SHRSP/IDmcr- fa rats. In the epididymal adipose tissue of the FR rats, Sirt1 expression was enhanced, as was adiponectin, whereas leptin was downregulation, findings that were paralleled by the serum protein levels. Furthermore, the serum ratio of high to total adiponectin was increased in the FR group. The mRNA expression of Sirt1 was upregulated in the adipose tissue in the FR group. Sirt1 mRNA expression was downregulated, while PPARα and GLUT2 expression was enhanced in the liver. No differences were found in terms of Sirt1, PPAR or GLUT4 expression in skeletal muscle. Significance These results indicate that FR corrects adipokine dysfunction by activating PPARγ via Sirt1 in adipose tissue. Furthermore, glucose and lipid metabolism are activated by upregulation of GLUT2 via the activation of PPARα in the liver.