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Chun-Mei Shi,
Yu-Mei Wang,
Chun-Mei Zhang,
Jie Qiu,
Ya-Hui Shen,
Jin-Gai Zhu,
Lin Chen,
Guang-Feng Xu, Ya-Ping Zhao,
Chen-Bo Ji,
Xi-Rong Guo
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ABSTRACT: NYGGF4 is a recently identified gene that is involved in obesity-associated insulin resistance. Previous data from this laboratory have demonstrated that NYGGF4 overexpression might contribute to the development of insulin resistance (IR) and to mitochondrial dysfunction. Additionally, NYGGF4 knockdown enhanced insulin sensitivity and mitochondrial function in 3T3-L1 adipocytes. We designed this study to determine whether silencing of NYGGF4 in 3T3-L1 adipocytes could rescue the effect of insulin sensitivity and mitochondrial function induced by the the cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP), a mitochondrion uncoupler, to ascertain further the mechanism of NYGGF4 involvement in obesity-associated insulin resistance. We found that 3T3-L1 adipocytes, incubated with 5μM FCCP for 12h, had decreased levels of insulin-stimulated glucose uptake and had impaired insulin-stimulated GLUT4 translocation. Silencing also diminished insulin-stimulated tyrosinephosphorylation of IRS-1 and serine phosphorylation of Akt. This phenomenon contrasts with the effect of NYGGF4 knockdown on insulin sensitivity and describes the regulatory function of NYGGF4 in adipocytes insulin sensitivity. We next analyzed the mitochondrial function in NYGGF4-silenced adipocytes incubated with FCCP. NYGGF4 knockdown partly rescued the dissipation of mitochondrial mass, mitochondrial DNA, intracellular ATP synthesis, and intracellular reactive oxygen species (ROS) production occurred following addition of FCCP, as well as inhibition of mitochondrial transmembrane potential (ΔΨm) in 3T3-L1 adipocytes incubated with FCCP Collectively, our results suggested that addition of silencing NYGGF4 partly rescued the effect of insulin resistance and mitochondrial dysfunction in NYGGF4 silenced 3T3-L1 adipocytes incubated with FCCP, which might explain the involvement of NYGGF4-induced IR and the development of NYGGF4 in mitochondrial function.
Mitochondrion 10/2012; · 3.62 Impact Factor
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Zhen-Ying Qin,
Min Zhang,
Xi-Rong Guo,
Yu-Mei Wang,
Guan-Zhong Zhu,
Yu-Hui Ni, Ya-Ping Zhao,
Jie Qiu,
Chun-Zhao Kou,
Rui Qin,
Xin-Guo Cao
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ABSTRACT: Overexpression of the Homo sapiens LYR motif containing 1 (LYRM1) causes mitochondrial dysfunction and induces insulin resistance in 3T3-L1 adipocytes. α-Lipoic acid (α-LA), a dithiol compound with antioxidant properties, improves glucose transport and utilization in 3T3-L1 adipocytes. The aim of this study was to investigate the direct effects of α-LA on reactive oxygen species (ROS) production and insulin sensitivity in LYRM1 overexpressing 3T3-L1 adipocytes and to explore the underlying mechanism. Pretreatment with α-LA significantly increased both basal and insulin-stimulated glucose uptake and insulin-stimulated GLUT4 translocation, while intracellular ROS levels in LYRM1 overexpressing 3T3-L1 adipocytes were decreased. These changes were accompanied by a marked upregulation in expression of insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt following treatment with α-LA. These results indicated that α-LA protects 3T3-L1 adipocytes from LYRM1-induced insulin resistance partially via its capacity to restore mitochondrial function and/or increase phosphorylation of IRS-1 and Akt.
Journal of Bioenergetics 07/2012; 44(5):579-86. · 2.81 Impact Factor
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Min Zhang,
Hai-Ming Zhao,
Zhen-Ying Qin,
Rui Qin,
Xiao-Hui Chen, Ya-Ping Zhao,
Chun-Mei Zhang,
Chun-Lin Gao,
Chun Zhu,
Chen-Bo Ji,
Xin-Guo Cao,
Xi-Rong Guo
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ABSTRACT: LYR motif containing 1 (LYRM1) is a novel gene that is abundantly expressed in the adipose tissue of obese subjects and is involved in insulin resistance. In this study, free fatty acids (FFAs) and tumor necrosis factor-α (TNF-α) are shown to upregulate LYRM1 mRNA expression in 3T3-L1 adipocytes. Conversely, resistin and rosiglitazone exert an inhibitory effect on LYRM1 mRNA expression. These results suggest that the expression of LYRM1 mRNA is affected by a variety of factors that are related to insulin sensitivity. LYRM1 may be an important mediator in the development of obesity-related insulin resistance.
Experimental Diabetes Research 01/2012; 2012:820989. · 1.20 Impact Factor
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ABSTRACT: Homo sapiens LYR motif containing 1 (LYRM1) is a recently discovered gene involved in adipose tissue homeostasis and obesity-associated insulin resistance. The exact mechanism by which LYRM1 induces insulin resistance has not yet been fully elucidated. In this study, we demonstrated that the overexpression of LYRM1 in 3T3-L1 adipocytes resulted in reduced insulin-stimulated glucose uptake, an abnormal mitochondrial morphology, and a decrease in intracellular ATP synthesis and mitochondrial membrane potential. In addition, LYRM1 overexpression led to excessive production of intracellular of reactive oxygen species. Collectively, our results indicated that the overexpression of LYRM1 caused mitochondrial dysfunction in adipocytes, which might be responsible for the development of LYRM1-induced insulin resistance.
Molecular Genetics and Metabolism 12/2010; 101(4):395-9. · 3.19 Impact Factor
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Xiao-Hui Chen, Ya-Ping Zhao,
Mei Xue,
Chen-Bo Ji,
Chun-Lin Gao,
Jin-Gai Zhu,
Da-Ni Qin,
Chun-Zhao Kou,
Xiao-Hong Qin,
Mei-Ling Tong,
Xi-Rong Guo
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ABSTRACT: TNF-alpha was the first proinflammatory cytokine identified linking obesity, insulin resistance and chronic inflammation. However, the mechanism of TNF-alpha in the etiology of insulin resistance is still far from clear. Because the mitochondria play an important role in energy metabolism, we investigated whether mitochondrial dysfunction is involved in pathogenesis of TNF-alpha-mediated insulin resistance. First, a fully differentiated insulin-resistant 3T3-L1 adipocyte model was established by incubating with 4 ng/ml TNF-alpha for 4 d, and then the mitochondrial morphology and functions were observed. TNF-alpha treatment induced pronounced morphological changes in the mitochondria, which became smaller and condensed, and some appeared hollow and absent of cristae. Mitochondrial dynamics changes were observed as increased mitofusion protein mfn1 and mitofission protein Drp1 levels compared with controls. No obvious effects on mitochondrial biogenesis were found. PGC-1alpha levels decreased, but no significant changes were found in mtTFA mRNA expression, NRF1mRNA expression and mitochondrial DNA (mtDNA). TNFalpha treatment also led to decreased mitochondrial membrane potential and reduced production of intracellular ATP, as well as accumulation of significant amounts of reactive oxygen species (ROS). Further research is required to determine if mitochondrial dysfunction is involved in the inflammatory mechanism of insulin resistance and may be a potential target for the treatment of insulin resistance.
Molecular and Cellular Endocrinology 10/2010; 328(1-2):63-9. · 4.19 Impact Factor
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ABSTRACT: Hyperglycemia and high free fatty acids (FFAs) are two well-known characteristics of type 2 diabetes, and are also implicated in the etiology of insulin resistance. However, their roles in mitochondrial dysfunction of white adipocytes are not well-studied. In this study, we investigated the effects of high glucose (25 mM), high free fatty acids (FFAs, 1mM), or a combination of both high glucose+high FFAs on mitochondrial function in differentiated 3T3-L1 adipocytes after 48 h of treatment. We found that high glucose, high FFAs, or high glucose+high FFAs reduced insulin-stimulated glucose uptake in differentiated 3T3-L1 adipocytes. In addition, the mitochondria became smaller and more compact. Levels of the mitofusion protein mfn1 decreased and levels of the mitofission protein Drp1 increased as compared to controls. NRF1 was downregulated, and PGC-1 beta levels were diminished in the high glucose and high glucose+high FFAs conditions. Levels of PGC-1 alpha and mtTFA mRNA were greatly downregulated. No difference was found in the mitochondrial DNA (mtDNA) and intracellular ATP levels of treated cells compared to control cells. Cells treated with high glucose or high FFAs accumulated significant amounts of reactive oxygen species (ROS) and displayed a loss of the mitochondrial membrane potential. High glucose and high glucose+high FFAs led to similar decreases in intramitochondrial calcium concentration, although high FFAs had no effect. Therefore, high glucose and high FFAs can regulate insulin sensitivity, and mitochondrial dysfunction may occur in this process.
Molecular and Cellular Endocrinology 02/2010; 320(1-2):25-33. · 4.19 Impact Factor
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ABSTRACT: Resveratrol, a member of a class of polyphenolic compounds known as flavonols, has been extensively studied for its anticancer, antiviral, anti-inflammatory, and neuroprotective roles. Caenorhabidits elegans is a well-established animal for investigating responses to radiation. We found that resveratrol may provide protection against hazardous radiation. Pre-treatment with resveratrol extended both the maximum and mean life span of irradiated C. elegans. Resveratrol acted as a strong radical scavenger and regulated superoxide dismutase (SOD) expression. In addition, resveratrol was shown to be capable of alleviating gamma-ray radiation exposure-induced reduction in mitochondrial SOD expression. Ultimately, a correlation may exist between dietary intake of trace amounts of resveratrol and anti-aging effects. A specific response mechanism may be activated after the administration of resveratrol in irradiated animals. Our results suggest the protective effect of resveratrol is due to its strong ability to protect from oxidative stress and protective effects in mitochondria. Therefore, resveratrol is potentially an effective protecting agent against irradiative damage.
Journal of Radiation Research 01/2010; 51(4):473-9. · 1.68 Impact Factor
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ABSTRACT: Uncoupling proteins (UCPs) belong to a superfamily of mitochondrial transporters that uncouple ATP synthesis from electron transport. We have previously shown that uncoupling protein 4 (UCP4) is differentially expressed in omental adipose tissue in diet-induced obese and normal rats. Overexpression of UCP4 promotes proliferation and inhibits apoptosis and differentiation of preadipocytes. In this work, we further characterized the effect of UCP4 on mitochondrial function in mature 3T3-L1 adipocytes. Transmission electron microscopy (TEM) showed that adipocytes overexpressing UCP4 displayed condensed mitochondria with twisted, condensed, and unclear cristae. Moreover, the loss of the mitochondrial membrane potential and intramitochondrial calcium was found. The adipocytes overexpressing UCP4 also showed decreased mitochondrial copy number (mtDNA) and lower mRNA expression of key factors in mitochondrial biogenesis, including PGC-1alpha and mtTFA. NRF-1 and ERRbeta levels were down-regulated, while NRF-2 levels were upregulated. In addition, UCP4 overexpression impaired mitochondrial fusion and fission, as indicated by decreased mitofusin mfn1, mfn2, and mitofission DRP1. When it came to total adipocytes, the UCP4 overexpressing adipocytes showed higher production reactive oxygen species and diminished levels of intracellular ATP. Furthermore, overexpression of UCP4 brought about impaired insulin sensitivity in adipocytes. UCP4 plays an important role in mitochondrial function and adipocyte insulin resistance. Its function deserves further attention.
International Journal of Molecular Medicine 01/2010; 25(1):71-80. · 1.98 Impact Factor
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ABSTRACT: Human STEAP4, a novel obesity-related gene, is associated with insulin sensitivity regulation in human adipocytes. This study aimed to explore the regulative role of TNFalpha on STEAP4 gene in matured human adipocytes.
Human preadipocytes were cultured and differentiated into matured adipocytes in vitro. Fully differentiated adipocytes (Day 17) were treated with different concentrations of TNFalpha (0, 5, 10, 25 and 50 ng/mL) for 24 hrs. Total RNA and protein were extracted from the adipocytes. Levels of STEAP4 mRNA and protein expression were determined by real-time quantitative RT-PCR and Western blot respectively.
Different concentrations (5, 10, 25 and 50 ng/mL) of TNFalpha treatment for 24 hrs resulted in a significant increase in the STEAP4 mRNA expression of human matured adipocytes.The maximal effect was seen in the 50 ng/mL of TNFalpha treatment group. In parallel, STEAP4 protein synthesis in matured adipocytes increased in response to TNFalpha treatment of different concentrations (5, 10, 25 and 50 ng/mL) for 24 hrs. The maximal up-regulated effect was seen in the 25 ng/mL of TNFalpha treatment group.
TNFalpha can up-regulate STEAP4 mRNA expression in human matured adipocytes.
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 12/2009; 11(12):1008-11.
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ABSTRACT: NYGGF4 is a novel gene that is abundantly expressed in the adipose tissue of obese subjects and is involved in insulin resistance. In the present study, the mRNA expression of NYGGF4 homologous genes was examined in the 3T3-L1 cell line. The NYGGF4 mRNAs were expressed at low levels in the 3T3-L1 preadipocytes. During the conversion of 3T3-L1 preadipocytes to adipocytes, the expression of NYGGF4 mRNA was upregulated. On the 8th day after induction of differentiation, the NYGGF4 mRNA levels peaked and remained high. Free fatty acids (FFA) and tumor necrosis factor-α (TNFα) could upregulate NYGGF4 mRNA expression in 3T3-L1 adipocytes, while interleukin-6 (IL-6), leptin, and resistin exerted an inhibitory effect. The results suggest that the expression of NYGGF4 mRNA is affected by a variety of factors that are related to insulin sensitivity. It is likely that NYGGF4 may be an important mediator in the development of obesity-related insulin resistance.
Molecular Biology Reports 11/2009; 37(7):3291-6. · 2.93 Impact Factor
