Protective Effect of Jiang Tang Xiao Ke Granules against Skeletal Muscle IR via Activation of the AMPK/SIRT1/PGC-1α Signaling Pathway.
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ABSTRACT:
SUBMITTER: Bai Y
PROVIDER: S-EPMC8277912 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Jiang Tang Xiao Ke (JTXK) granule, a Chinese herbal formula, has been used clinically to treat type 2 diabetes (T2DM) for decades. Our previous studies showed that JTXK granule exhibited anti-diabetic and anti-oxidative functions in experimental diabetic rats induced by a high fat diet and streptozotocin. However, the underlying mechanisms remain poorly understood. Herein, we aimed to investigate the therapeutic effect of JTXK granule on T2DM KKAy mice and the possible associations with skeletal muscle in the current study. Our results showed that JTXK granule significantly reduced food intake and body weight in T2DM KKAy mice. JTXK granule treatment also decreased the blood glucose and HbA1c levels and increased the insulin sensitivity in a time-dependent manner. Additionally, it ameliorated hyperlipidaemia and induced a lower free fatty acid level, displaying an effect on disorders of lipid metabolism. JTXK granule significantly increased the expression of insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI3K), protein kinase B (PKB/Akt) and glucose transporter 4 (Glut4) and decreased the expression of glycogen synthase kinase 3β (GSK3β). We concluded that JTXK granule is an effective drug for T2DM through regulating the PI3K/Akt signalling pathway in skeletal muscle.
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Project description:Objective:To investigate the impact of JTXK granule on the miRNA expression profiles in hepatic tissue of diabetic mice, and to explore the molecular targets and associated signaling pathways of JTXK granule in its anti-diabetic effect. Methods:Eight mice were randomly selected as normal group fed with chow diet. Then high fat diet was used to induce diabetic model, and the mice were subsequently divided into JTXK-treated group (J group, n = 6) and model group (M group, n = 6). After 8 weeks' intervention we examined the fasting blood glucose and observed the histopathologic changes in hepatic tissue between these two groups. Next we screened the differentially expressed miRNAs between the two groups using microRNA sequencing analysis. Finally, miRNA target gene prediction, GO and KEGG analysis were applied to explore the function of DEMs. Results:The blood glucose level in J group was significantly lower than M group (P < 0.05). The results from H&E staining showed that the arrangement and structure of hepatocytes from J group were basically normal with fewer ballooning degeneration and less inflammatory cell infiltration. Furthermore, a total of 33 significantly differentiated miRNAs were detected in comparison between the two groups (| log2(fold change) | >0.3, P < 0.05). MiRNA-mRNA analysis showed that mmu-miR-30a-5p, mmu-miR-23b-5p, mmu-miR-199a-5p, mmu-miR-425-5p, and mmu-miR-214-3p are closely related to inflammatory response, histological changes and insulin signal transduction in liver. In addition, KEGG analysis showed that the DEMs were closely related to Ras and insulin signaling pathway. Conclusion:JTXK granule exerts anti-diabetic effect in hepatic tissue of diabetic mice by modulating miRNAs and mRNAs network.
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Project description:Purpose: To investigate the effect of JTXK granule on the expression pattern of miRNA in pancreatic tissue of KKAy diabetic mice, and to explore the molecular mechanism and pathways of JTXK granule in anti-diabetic effect. Methods: We used high fat diet (HFD) to induce the KKAy diabetic mice and screened the differentially expressed miRNAs (DEMs) between JTXK-treated group (n = 6) and the diabetic group (n = 6) using MicroRNA (miRNA) Microarray. C57BL/6J mice were given a normal diet as the control group (n = 6). Subsequently, miRNA target gene prediction, GO and Pathway analysis were used to explore the function of DEMs. Finally, the mechanism of anti-diabetic effects of JTXK granule was tested by in vitro INS-1 pancreatic β-cell experiment. Results: The blood glucose and body weight of JTXK-treated group was significantly lower compared with the model group. Moreover, a total of 45 miRNAs with significant differences were detected in the model group and the JTXK-treated group (P ≤ 0.05, Fold Change > 2). Further, miRNA-mRNA analysis showed that the differential expression of mmu-miR-192-5p, mmu-miR-291a-3p, mmu-miR-320-3p, mmu-miR-139-5p and mmu-miR-378a-3p are closely related to pancreatic histological changes. In addition, pathway analysis showed that the DEMs were closely related to PI3K-Akt Signaling Pathway. Furthermore, the levels of serine/threonine-protein kinase (Akt), phosphorylated Akt (p-Akt) and phosphorylated forkhead transcription factor O1 (p-Foxo1) in INS-1-FOXO1 overexpressing model cells were lower than those in normal group, while JTXK granules could increase the expression of Akt, p-Akt and p-Foxo1. Conclusions: The results showed that JTXK granule could play an anti-diabetic role by regulating the mRNA and miRNAs associated with PI3K-Akt pathway in diabetic mice pancreatic tissue.
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Project description:Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes exerts strong antihyperglycemic and triglyceride-lowering effects and reduction of body weight. Despite the importance of FGF21 in the regulation of glucose, lipid, and energy homeostasis, the mechanisms by which FGF21 functions as a metabolic regulator remain largely unknown. Here we demonstrate that FGF21 regulates energy homeostasis in adipocytes through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), resulting in enhanced mitochondrial oxidative function. AMPK phosphorylation levels were increased by FGF21 treatment in adipocytes as well as in white adipose tissue from ob/ob mice. FGF21 treatment increased cellular NAD(+) levels, leading to activation of SIRT1 and deacetylation of its downstream targets, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and histone 3. Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1alpha activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an AMPK-SIRT1-PGC1alpha-dependent mechanism in adipocytes.
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Project description:Adiponectin is an adipocyte-secreted adipokine with pleiotropic actions. Clinical evidence has shown that serum adiponectin levels are increased and that adiponectin can protect pancreatic beta cells against apoptosis, which suggests that adiponectin may play an anti-apoptotic role in pancreatic cancer (PC). Here, we investigated the effects of adiponectin on PC development and elucidated the underlying molecular mechanisms. Adiponectin deficiency markedly attenuated pancreatic tumorigenesis in vivo. We found that adiponectin significantly inhibited the apoptosis of both human and mouse pancreatic cancer cells via adipoR1, but not adipoR2. Furthermore, adiponectin can increase AMP-activated protein kinase (AMPK) phosphorylation and NAD-dependent deacetylase sirtuin-1 (Sirt1) of PC cells. Knockdown of AMPK or Sirt1 can increase the apoptosis in PC cells. AMPK up-regulated Sirt1, and Sirt1 can inversely phosphorylate AMPK. Further studies have shown that Sirt1 can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which can increase the expression levels of mitochondrial genes. Thus, adiponectin exerts potent anti-apoptotic effects on PC cells via the activation of AMPK/Sirt1/PGC1α signaling. Finally, adiponectin can elevate β-catenin levels. Taken together, these novel findings reveal an unconventional role of adiponectin in promoting pancreatic cancers, and suggest that the effects of adiponectin on tumorigenesis are highly tissue-dependent.
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Project description:The diabetes medication canagliflozin (Cana) is a sodium glucose cotransporter 2 (SGLT2) inhibitor acting by increasing urinary glucose excretion and thus reducing hyperglycaemia. Cana treatment also reduces body weight. However, it remains unclear whether Cana could directly work on adipose tissue. In the present study, the pharmacological effects of Cana and the associated mechanism were investigated in adipocytes and mice. Stromal-vascular fractions (SVFs) were isolated from subcutaneous adipose tissue and differentiated into mature adipocytes. Our results show that Cana treatment directly increased cellular energy expenditure of adipocytes by inducing mitochondrial biogenesis independently of SGLT2 inhibition. Along with mitochondrial biogenesis, Cana also increased mitochondrial oxidative phosphorylation, fatty acid oxidation and thermogenesis. Mechanistically, Cana promoted mitochondrial biogenesis and function via an Adenosine monophosphate-activated protein kinase (AMPK) - silent information regulator 1 (Sirt1) - peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α) signalling pathway. Consistently, in vivo study demonstrated that Cana increased AMPK phosphorylation and the expression of Sirt1 and Pgc-1α. The present study reveals a new therapeutic function for Cana in regulating energy homoeostasis.AbbreviationsUcp-1, uncoupling protein 1; cAMP, cyclic adenosine monophosphate; PKA, cAMP-dependent protein kinase A; SGLT, sodium glucose cotransporter; Cana, canagliflozin; T2DM: type 2 diabetes; Veh, vehicle; Pgc-1α, peroxisome proliferator-activated receptor γ coactivator-1α; SVFs, stromal-vascular fractions; FBS, bovine serum; Ad, adenovirus; mtDNA, mitochondrial DNA; COX2, cytochrome oxidase subunit 2; RT-PCR, real-time PCR; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; Prdm16, PR domain zinc finger protein 16; Cidea, cell death inducing DFFA-like effector A; Pgc-1β, peroxisome proliferator-activated receptor γ coactivator-1β; NRF1, nuclear respiratory factor 1; Tfam, mitochondrial transcription factor A; OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation; AMPK, Adenosine monophosphate-activated protein kinase; p-AMPK, phosphorylated AMPK; Sirt1, silent information regulator 1; mTOR, mammalian target of rapamycin; WAT, white adipose tissue; Fabp4, fatty acid binding protein 4; Lpl, lipoprotein lipase; Slc5a2, solute carrier family 5 member 2; ERRα, oestrogen related receptor α; Uqcrc2, ubiquinol-cytochrome c reductase core protein 2; Uqcrfs1, ubiquinol-cytochrome c reductase, Rieske iron-sulphur polypeptide 1; Cox4, cytochrome c oxidase subunit 4; Pparα, peroxisome proliferator activated receptor α; NAD+, nicotinamide adenine dinucleotide; Dio2, iodothyronine deiodinase 2; Tmem26, transmembrane protein 26; Hoxa9, homeobox A9; FCCP, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; Rot/AA, rotenone/antimycin A; OCR, oxygen consumption rate; Pparγ, peroxisome proliferator activated receptor γ; C/ebp, CCAAT/enhancer binding protein; LKB1, liver kinase B1; AUC, area under the cure; Vd, apparent volume of distribution.
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Project description:SIRT3 is a member of the sirtuin family of NAD(+)-dependent deacetylases, which is localized to the mitochondria and is enriched in kidney, brown adipose tissue, heart, and other metabolically active tissues. We report here that SIRT3 responds dynamically to both exercise and nutritional signals in skeletal muscle to coordinate downstream molecular responses. We show that exercise training increases SIRT3 expression as well as associated CREB phosphorylation and PGC-1alpha up-regulation. Furthermore, we show that SIRT3 is more highly expressed in slow oxidative type I soleus muscle compared to fast type II extensor digitorum longus or gastrocnemius muscles. Additionally, we find that SIRT3 protein levels in skeletal muscle are sensitive to diet, for SIRT3 expression increases by fasting and caloric restriction, yet it is decreased by high-fat diet. Interestingly, the caloric restriction regimen also leads to phospho-activation of AMPK in muscle. Conversely in SIRT3 knockout mice, we find that the phosphorylation of both AMPK and CREB and the expression of PGC-1alpha are down regulated, suggesting that these key cellular factors may be important components of SIRT3-mediated biological signals in vivo.
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Project description:Xiao Ke Yin Shui (XKYS) formula is a traditional Chinese medicine formula treating type 2 diabetes mellitus (T2DM). XKYS formula consists of four herbs, i.e., Coptidis rhizoma, Liriopes radix, bitter melon, and Cassiae semen. Herein, the chemical profiles of four herb extracts were investigated, and further analysis of the underlying mechanism of XKYS formula treating T2DM was performed using network pharmacology. The main components were selected for our network-based research. Targets of XKYS formula were mainly collected from two databases, SwissTargetPrediction and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the text-mining method was also implemented. T2DM relating genes and therapeutic targets were collected from five databases. Subsequently, STRING and Cytoscape were employed for the analysis of protein-protein interaction (PPI) networks. Functional annotation and pathway analysis were conducted to investigate the functions and relating pathways of target genes. The content of 12 compounds in the herb extracts was determined. With the analysis of PPI networks, a total of 76 genes were found to be important nodes and could be defined as the main target genes regulated by XKYS formula in the treatment of T2DM and its complications. Components in XKYS formula mainly regulate proteins including protein kinase B (Akt), phosphatidylinositol 3-kinase (PI3K), insulin receptor substrate (IRS), and tumor necrosis factor (TNF). XKYS formula exerts therapeutic effects in a synergetic manner and exhibits antidiabetic effect mainly via reducing insulin resistance. These findings could be guidelines in the further investigation of this formula.
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Project description:Excessive fat accumulation has been considered as a major contributing factor for muscle mitochondrial dysfunction and its associated metabolic complications. The purpose of present study is to investigate a role of vitamin D in muscle fat accumulation and mitochondrial changes. In differentiated C2C12 muscle cells, palmitic acid (PA) was pretreated, followed by incubation with 1,25-dihyroxyvitamin D (1,25(OH)2D) for 24 h. PA led to a significant increment of triglyceride (TG) levels with increased lipid peroxidation and cellular damage, which were reversed by 1,25(OH)2D. The supplementation of 1,25(OH)2D significantly enhanced PA-decreased mtDNA levels as well as mRNA levels involved in mitochondrial biogenesis such as nuclear respiratory factor 1 (NRF1), peroxisome proliferative activated receptor gamma coactivator-1? (PGC-1?), and mitochondrial transcription factor A (Tfam) in C2C12 myotubes. Additionally, 1,25(OH)2D significantly increased ATP levels and gene expression related to mitochondrial function such as carnitine palmitoyltransferase 1 (CPT1), peroxisome proliferator-activated receptor ? (PPAR?), very long-chain acyl-CoA dehydrogenase (VLCAD), long-chain acyl-CoA dehydrogenase (LCAD), medium-chain acyl-CoA dehydrogenase (MCAD), uncoupling protein 2 (UCP2), and UCP3 and the vitamin D pathway including 25-dihydroxyvitamin D3 24-hydroxylase (CYP24) and 25-hydroxyvitamin D3 1-alpha-hydroxylase (CYP27) in PA-treated C2C12 myotubes. In addition to significant increment of sirtuin 1 (SIRT1) mRNA expression, increased activation of adenosine monophosphate-activated protein kinase (AMPK) and SIRT1 was found in 1,25(OH)2D-treated C2C12 muscle cells. Thus, we suggest that the observed protective effect of vitamin D on muscle fat accumulation and mitochondrial dysfunction in a positive manner via modulating AMPK/SIRT1 activation.
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