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ABSTRACT: Recent studies have revealed that the central nervous system (CNS), particularly the hypothalamus, is critical for regulating insulin sensitivity in peripheral tissues. The aim of our current study is to investigate the possible involvement of hypothalamic Activating Transcription Factor (ATF) 4 in the regulation of insulin sensitivity in the liver. Here, we show that overexpression of ATF4 in the hypothalamus resulting from intraventricular (icv) injection of adenovirus expressing ATF4 induces hepatic insulin resistance in mice and that inhibition of hypothalamic ATF4 by icv adenovirus expressing a dominant-negative ATF4 variant has the opposite effect. We also show that hypothalamic ATF4-induced insulin resistance is significantly blocked by selective hepatic vagotomy or by inhibiting activity of the mammalian target of rapamycin (mTOR) downstream target S6K1. Finally, we show that inhibition of hypothalamic ATF4 reverses hepatic insulin resistance induced by acute brain endoplasmic reticulum (ER) stress. Taken together, our study describes a novel central pathway regulating hepatic insulin sensitivity that is mediated by hypothalamic ATF4/mTOR/S6K1 signaling and the vagus nerve, and demonstrate an important role for hypothalamic ATF4 in brain ER stress-induced hepatic insulin resistance. These results may lead to the identification of novel therapeutic targets for treating insulin resistance and associated metabolic diseases.
Diabetes 03/2013; · 8.29 Impact Factor
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ABSTRACT: It is well established that the central nervous system (CNS), especially the hypothalamus, plays an important role in regulating energy homeostasis and lipid metabolism. We have previously shown that hypothalamic corticotropin-releasing hormone (CRH) is critical for stimulating fat loss in response to dietary leucine deprivation. The molecular mechanisms underlying the CNS regulation of leucine deprivation-stimulated fat loss are, however, still largely unknown. Here, we used intracerebroventricular injection of adenoviral vectors to identify a novel role for hypothalamic p70 S6 kinase 1 (S6K1), a major downstream effector of the kinase mammalian target of rapamycin, in leucine deprivation stimulation of energy expenditure. Furthermore, we show that the effect of hypothalamic S6K1 is mediated by modulation of Crh expression in a melanocortin-4 receptor-dependent manner. Taken together, our studies provide a new perspective for understanding the regulation of energy expenditure by the CNS and the importance of cross-talk between nutritional control and regulation of endocrine signals.
Diabetes 07/2012; 61(10):2461-71. · 8.29 Impact Factor
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ABSTRACT: To evaluate and compare the dynamic changes in functional loading or non-functional loading with platform-switching (PLS) implants and butt-joint implants,and to refine the factors leading to marginal bone loss around PLS.
Six adult dogs were selected and numbered randomly.The second,third and fourth premolars in bilateral mandible of each dog were extracted. After 3 months, the implantation operation was carried out. There were 3 kinds of implants, 36 implants in total, which were divided in to 3 groups: Group A,Group G and Group U. In particular order, A, G and U were placed on each side of every dog. Three months later, the 2nd surgery was begun. At the 4th month from the 1st surgery, for each dog, on the right side only, the abutments were installed and impression was taken. Then, after 2 weeks, the dental prostheses were put on. All dogs were executed at the end of the 12th month. X-ray film was taken at the 3rd, 6th, 9th and 12th month and the moment of the 1st surgery (baseline). Measurements were made between the implant shoulder (IS),the most coronal level of bone in contact with implant (CLB), and the level of alveolar bone crest (BC). According to the different groups of implants (A, G, U), all records were analyzed with paired and Wilcoxon's signed rank test using SPSS11.5 software package.
The mean IS-CLB and IS-BC values of group A, G were significantly different with those of group U at the 6th, 9th and 12th month, while there was no significant difference between group A and G. No matter they were loading or not, the self-comparison of each kind of implant presented no significant difference. There was no significant difference between every kind of implant on their self-comparison during the first three months; while, the differences were significant during the next 9 months.
The most significant changes in the absorption of marginal bone around two stage submerged implant can be observed after 3 months of implanting. The bone absorption was not related to functional loading or not.
Shanghai kou qiang yi xue = Shanghai journal of stomatology 02/2012; 21(1):41-7.
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ABSTRACT: To investigate USMM coupled techniques applied in active ingredient extraction and separation of Salvia.
Supercritical fluid extraction (SFE) CO2 was used to extract and separate tanshinone liposoluble constituent, ultrasonic was used to extract danshen phenolic acids ternate, membrane separation and macroporous resin was used to purify water extraction from HDP. Transfer rate and purity of Danshen active ingredients were employed as the investigation indexes, the feasibility of USMM technology used in extraction and separation S. miltiorrhiza was investigated.
SFE-CO2 extraction process for S. miltiorrhiza was stable and feasible. Danshen phenolic acids extracted from slag of SFE-CO2 by ultrasound got a high yield. Macroporous resin purification technology could improve the purity of active ingredients of S. miltiorrhiza. Membrane separation and membrane separation coupled with macroporous resin technology applied to the purification process of S. miltiorrhiza phenolic acids still needed further research.
It is feasible basically that USMM technology apply in extraction and separation of Salvia active ingredient.
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 11/2011; 36(22):3104-7.
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Ying Cheng,
Qian Zhang,
Qingshu Meng,
Tingting Xia,
Zhiying Huang,
Chunxia Wang,
Bin Liu,
Shanghai Chen, Fei Xiao,
Ying Du,
Feifan Guo
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ABSTRACT: We previously showed that leucine deprivation decreases abdominal fat mass largely by increasing energy expenditure, as demonstrated by increased lipolysis in white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). The goal of the present study was to investigate the possible involvement of central nervous system (CNS) in this regulation and elucidate underlying molecular mechanisms. For this purpose, levels of genes and proteins related to lipolysis in WAT and UCP1 expression in BAT were analyzed in wild-type mice after intracerebroventricular administration of leucine or corticotrophin-releasing hormone antibodies, or in mice deleted for three β-adrenergic receptors, after being maintained on a leucine-deficient diet for 7 d. Here, we show that intracerebroventricular administration of leucine significantly attenuates abdominal fat loss and blocks activation of hormone sensitive lipase in WAT and induction of UCP1 in BAT in leucine-deprived mice. Furthermore, we provide evidence that leucine deprivation stimulates fat loss by increasing expression of corticotrophin-releasing hormone in the hypothalamus via activation of stimulatory G protein/cAMP/protein kinase A/cAMP response element-binding protein pathway. Finally, we show that the effect of leucine deprivation on fat loss is mediated by activation of the sympathetic nervous system. These results suggest that CNS plays an important role in regulating fat loss under leucine deprivation and thereby provide novel and important insights concerning the importance of CNS leucine in the regulation of energy homeostasis.
Molecular Endocrinology 06/2011; 25(9):1624-35. · 4.54 Impact Factor
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ABSTRACT: Chronic feeding of HCD (high-carbohydrate diet) is one of the major contributors to the prevailing of metabolic diseases. ATF4 (activating transcription factor 4) has been shown to play an important role in the regulation of glucose metabolism and obesity development; however, it is unclear how ATF4(-/-) mice respond to HCD. In the present study, we show that 8 weeks of HCD results in significant higher accumulation of TAGs (triacylglycerols) in livers and impairment in glucose tolerance in ATF4(+/+) mice, but not in ATF4(-/-) mice, compared with those on a normal diet. Meanwhile, energy expenditure is further enhanced by HCD in ATF4(-/-) mice. Moreover, we show that ATF4 deficiency suppresses HCD-induced SCD1 (stearoyl-CoA desaturase 1) expression, furthermore, oral supplementation of the main product of SCD1 oleate (18:1) increases TAG accumulation in livers of ATF4(-/-) mice. Taken together, these results suggest that ATF4 deficiency is protective for HCD-induced hepatic steatosis and impairment of glucose tolerance and insulin sensitivity. Furthermore, the resistance to hepatic steatosis is at least in part due to suppression of SCD1 expression under HCD.
Biochemical Journal 06/2011; 438(2):283-9. · 4.90 Impact Factor
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Fei Xiao,
Zhiying Huang,
Houkai Li,
Junjie Yu,
Chunxia Wang,
Shanghai Chen,
Qingshu Meng,
Ying Cheng,
Xiang Gao,
Jia Li,
Yong Liu,
Feifan Guo
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ABSTRACT: We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms.
Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation.
We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation-increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions.
This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases.
Diabetes 01/2011; 60(3):746-56. · 8.29 Impact Factor
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ABSTRACT: White adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduction in abdominal fat mass. The cellular mechanisms responsible for this loss, however, are unclear. The goal of current study is to investigate possible mechanisms.
Male C57BL/6J mice were fed either control, leucine-deficient, or pair-fed diets for 7 days. Changes in metabolic parameters and expression of genes and proteins related to lipid metabolism were analyzed in WAT and BAT.
We found that leucine deprivation for 7 days increases oxygen consumption, suggesting increased energy expenditure. We also observed increases in lipolysis and expression of beta-oxidation genes and decreases in expression of lipogenic genes and activity of fatty acid synthase in WAT, consistent with increased use and decreased synthesis of fatty acids, respectively. Furthermore, we observed that leucine deprivation increases expression of uncoupling protein (UCP)-1 in BAT, suggesting increased thermogenesis.
We show for the first time that elimination of dietary leucine produces significant metabolic changes in WAT and BAT. The effect of leucine deprivation on UCP1 expression is a novel and unexpected observation and suggests that the observed increase in energy expenditure may reflect an increase in thermogenesis in BAT. Further investigation will be required to determine the relative contribution of UCP1 upregulation and thermogenesis in BAT to leucine deprivation-stimulated fat loss.
Diabetes 10/2009; 59(1):17-25. · 8.29 Impact Factor
