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Safflower yellow improves insulin sensitivity in high-fat diet-induced obese mice by promoting peroxisome proliferator-activated receptor-?2 expression in subcutaneous adipose tissue.

ABSTRACT: AIMS/INTRODUCTION:Safflower yellow (SY) and its main component, hydroxysafflor yellow A, have been demonstrated to show anti-obesity effects. Peroxisome proliferator-activated receptor-?2 (PPAR?2) is a critical transcription factor in adipose tissue metabolism. The aim of the present study was to explore the effects of SY in high-fat diet-induced obese mice, and further investigate the mechanism involving PPAR?2. METHODS:High-fat diet-induced obese mice were given 120 mg/kg/day SY for 8 weeks. Glucose and insulin tolerance tests were carried out. Fat mass and serum levels of glucose and insulin were measured. The expression of insulin signaling pathway-related genes and PPAR?2 in the adipose tissue was measured. In vitro, the effects of SY (0-500 mg/L) and hydroxysafflor yellow A (0-100 mg/L) on PPAR?2 promoter activities and PPAR?2 messenger ribonucleic acid (mRNA) levels in 3T3-L1 preadipocytes or adipocytes were also detected. RESULTS:Safflower yellow reduced fat mass, decreased glucose levels and improved insulin sensitivity in obese mice. SY also increased the mRNA levels of insulin signaling pathway-related genes, and increased PPAR?2 mRNA levels by 39.1% in subcutaneous adipose tissue (P < 0.05). In vitro, SY and hydroxysafflor yellow A significantly enhanced PPAR?2 promoter activities by 1.3-2.1-fold, and increased PPAR?2 mRNA levels by 1.2-1.6-fold in 3T3-L1 preadipocytes or adipocytes (P < 0.05). CONCLUSIONS:SY could reduce fat mass, decrease glucose levels and improve insulin sensitivity in high-fat diet-induced obese mice. The probable mechanism is to increase PPAR?2 expression by stimulating PPAR?2 promoter activities, further increasing the expression of insulin signaling pathway-related genes in subcutaneous adipose tissue.

SUBMITTER: Yan K

PROVIDER: S-EPMC7610129 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Safflower yellow improves insulin sensitivity in high-fat diet-induced obese mice by promoting peroxisome proliferator-activated receptor-γ2 expression in subcutaneous adipose tissue.

Yan Kemin K Wang Xiangqing X Zhu Huijuan H Pan Hui H Wang Linjie L Yang Hongbo H Liu Meijuan M Jin Ming M Zang Baoxia B Gong Fengying F

Journal of diabetes investigation 20200605 6

<h4>Aims/introduction</h4>Safflower yellow (SY) and its main component, hydroxysafflor yellow A, have been demonstrated to show anti-obesity effects. Peroxisome proliferator-activated receptor-γ2 (PPARγ2) is a critical transcription factor in adipose tissue metabolism. The aim of the present study was to explore the effects of SY in high-fat diet-induced obese mice, and further investigate the mechanism involving PPARγ2.<h4>Methods</h4>High-fat diet-induced obese mice were given 120 mg/kg/day SY ...[more]

PMID: 32356607

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Project description:ObjectivesSafflower yellow (SY) is the main effective ingredient of Carthamus tinctorius L. It has been reported that SY plays an important role in anti-inflammation, anti-platelet aggregation, and inhibiting thrombus formation. In present study, we try to investigate the effects of SY on body weight, body fat mass, insulin sensitivity in high fat diet (HFD)-induced obese mice.MethodsHFD-induced obese male ICR mice were intraperitoneally injected with SY (120 mg kg(-1)) daily. Eight weeks later, intraperitoneal insulin tolerance test (IPITT), and intraperitoneal glucose tolerance test (IPGTT) were performed, and body weight, body fat mass, serum insulin levels were measured. The expression of glucose and lipid metabolic related genes in white adipose tissue (WAT) were determined by RT-qPCR and western blot technologies.ResultsThe administration obese mice with SY significantly reduced the body fat mass of HFD-induced obese mice (P < 0.05). IPITT test showed that the insulin sensitivity of SY treated obese mice were evidently improved. The mRNA levels of insulin signaling pathway related genes including insulin receptor substrate 1(IRS1), PKB protein kinase (AKT), glycogen synthase kinase 3? (GSK3?) and forkhead box protein O1(FOXO1) in mesenteric WAT of SY treated mice were significantly increased to 1.9- , 2.8- , 3.3- , and 5.9-folds of that in HFD-induced control obese mice, respectively (P < 0.05). The protein levels of AKT and GSK3? were also significantly increased to 3.0 and 5.2-folds of that in HFD-induced control obese mice, respectively (P < 0.05). Meanwhile, both the mRNA and protein levels of peroxisome proliferator-activated receptorgamma coactivator 1? (PGC1?) in inguinal subcutaneous WAT of SY group were notably increased to 2.5 and 3.0-folds of that in HFD-induced control obese mice (P < 0.05).ConclusionsSY significantly reduce the body fat mass, fasting blood glucose and increase insulin sensitivity of HFD-induced obese mice. The possible mechanism is to promote the browning of subcutaneous WAT and activate the IRS1/AKT/GSK3? pathway in visceral WAT. Our study provides an important experimental evidence for developing SY as a potential anti-obesity and anti-diabetic drug.

Project description:ObjectiveNuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice.MethodsA novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were administered with WO95E for 4 weeks. Insulin sensitivity, glucose tolerance, body weight, fat tissue weight, adipocyte size, morphology, energy expenditure, and expression levels of genes involved in PPARγ activity, thermogenesis/browning, and TZD-related side effects were evaluated.ResultsWO95E binds to PPARγ with high affinity and acts as a PPARγ partial agonist. WO95E inhibits PPARγ phosphorylation and regulates PPARγ phosphorylation-dependent genes. WO95E ameliorates insulin resistance and glucose tolerance in mice of diet-induced obesity, with minimal TZD use-associated side effects. We found that WO95E promotes white-to-brown adipocyte conversion and energy expenditure and hence protects against diet-induced obesity. WO95E decreases the size of adipocytes and suppresses adipose tissue inflammation. WO95E also suppresses obesity-associated liver steatosis.ConclusionsWO95E improves insulin sensitivity and glucose homeostasis and promotes browning and energy expenditure by acting as a novel PPARγ phosphorylation inhibitor/partial agonist. Our findings suggest the potential of this compound or its derivative for the therapeutic treatment of insulin resistance and obesity.

Dataset Information

Safflower yellow improves insulin sensitivity in high-fat diet-induced obese mice by promoting peroxisome proliferator-activated receptor-?2 expression in subcutaneous adipose tissue.

Publications

Safflower yellow improves insulin sensitivity in high-fat diet-induced obese mice by promoting peroxisome proliferator-activated receptor-γ2 expression in subcutaneous adipose tissue.

Similar Datasets

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