共查询到20条相似文献,搜索用时 15 毫秒
1.
Haemmerle G Lass A Zimmermann R Gorkiewicz G Meyer C Rozman J Heldmaier G Maier R Theussl C Eder S Kratky D Wagner EF Klingenspor M Hoefler G Zechner R 《Science (New York, N.Y.)》2006,312(5774):734-737
Fat tissue is the most important energy depot in vertebrates. The release of free fatty acids (FFAs) from stored fat requires the enzymatic activity of lipases. We showed that genetic inactivation of adipose triglyceride lipase (ATGL) in mice increases adipose mass and leads to triacylglycerol deposition in multiple tissues. ATGL-deficient mice accumulated large amounts of lipid in the heart, causing cardiac dysfunction and premature death. Defective cold adaptation indicated that the enzyme provides FFAs to fuel thermogenesis. The reduced availability of ATGL-derived FFAs leads to increased glucose use, increased glucose tolerance, and increased insulin sensitivity. These results indicate that ATGL is rate limiting in the catabolism of cellular fat depots and plays an important role in energy homeostasis. 相似文献
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Endogenous opioid binding to micro receptors is hypothesized to mediate natural rewards and has been proposed to be the basis of infant attachment behavior. Here, we report that micro-opioid receptor knockout mouse pups emit fewer ultrasonic vocalizations when removed from their mothers but not when exposed to cold or male mice odors. Moreover these knockout pups do not show a preference toward their mothers' cues and do not show ultrasonic calls potentiation after brief maternal exposure. Results from this study may indicate a molecular mechanism for diseases characterized by deficits in attachment behavior, such as autism or reactive attachment disorder. 相似文献
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Caterina MJ Leffler A Malmberg AB Martin WJ Trafton J Petersen-Zeitz KR Koltzenburg M Basbaum AI Julius D 《Science (New York, N.Y.)》2000,288(5464):306-313
The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia. 相似文献
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Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene 总被引:1,自引:0,他引:1
Elchebly M Payette P Michaliszyn E Cromlish W Collins S Loy AL Normandin D Cheng A Himms-Hagen J Chan CC Ramachandran C Gresser MJ Tremblay ML Kennedy BP 《Science (New York, N.Y.)》1999,283(5407):1544-1548
Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity. 相似文献
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Zimmermann R Strauss JG Haemmerle G Schoiswohl G Birner-Gruenberger R Riederer M Lass A Neuberger G Eisenhaber F Hermetter A Zechner R 《Science (New York, N.Y.)》2004,306(5700):1383-1386
Mobilization of fatty acids from triglyceride stores in adipose tissue requires lipolytic enzymes. Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Until now, hormone-sensitive lipase (HSL) was the only enzyme known to hydrolyze triglycerides in mammalian adipose tissue. Here, we report that a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis. It is interesting that ATGL contains a "patatin domain" common to plant acyl-hydrolases. ATGL is highly expressed in adipose tissue of mice and humans. It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. Inhibition of ATGL markedly decreases total adipose acyl-hydrolase activity. Thus, ATGL and HSL coordinately catabolize stored triglycerides in adipose tissue of mammals. 相似文献
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Limb and skin abnormalities in mice lacking IKKalpha 总被引:1,自引:0,他引:1
Takeda K Takeuchi O Tsujimura T Itami S Adachi O Kawai T Sanjo H Yoshikawa K Terada N Akira S 《Science (New York, N.Y.)》1999,284(5412):313-316
The gene encoding inhibitor of kappa B (IkappaB) kinase alpha (IKKalpha; also called IKK1) was disrupted by gene targeting. IKKalpha-deficient mice died perinatally. In IKKalpha-deficient fetuses, limb outgrowth was severely impaired despite unaffected skeletal development. The epidermal cells in IKKalpha-deficient fetuses were highly proliferative with dysregulated epidermal differentiation. In the basal layer, degradation of IkappaB and nuclear localization of nuclear factor kappa B (NF-kappaB) were not observed. Thus, IKKalpha is essential for NF-kappaB activation in the limb and skin during embryogenesis. In contrast, there was no impairment of NF-kappaB activation induced by either interleukin-1 or tumor necrosis factor-alpha in IKKalpha-deficient embryonic fibroblasts and thymocytes, indicating that IKKalpha is not essential for cytokine-induced activation of NF-kappaB. 相似文献
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Bohn LM Lefkowitz RJ Gainetdinov RR Peppel K Caron MG Lin FT 《Science (New York, N.Y.)》1999,286(5449):2495-2498
The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the mu opioid receptor (muOR). The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with beta-arrestin 1 and beta-arrestin 2. Functional deletion of the beta-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that muOR desensitization was impaired. These results provide evidence in vivo for the physiological importance of beta-arrestin 2 in regulating the function of a specific GPCR, the muOR. Moreover, they suggest that inhibition of beta-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence. 相似文献
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为分析两种脂肪供能条件下3种不同油脂饮食对小鼠腹股沟皮下脂肪沉积及其巨噬细胞分型的影响,90只C57BL/6J小鼠被随机分为6组,分别饲喂低脂猪油(Lar-10%)、低脂菜籽油(Rap-10%)、低脂橄榄油(Oli-10%)、高脂猪油(Lar-30%)、高脂菜籽油(Rap-30%)和高脂橄榄油(Oli-30%),16周后解剖取腹股沟皮下脂肪组织,并对其进行苏木精-伊红染色,活性氧(Reactive oxygen species,ROS)含量检测,M1、M2型巨噬细胞标记物(CD11c和CD206)荧光双染,并通过ELISA检测其含量。结果表明:1)在低脂饮食条件下,三种油脂对小鼠腹股沟皮下脂肪组织重量、脂肪细胞横截面积、腹股沟皮下脂肪ROS含量均无显著影响(P>0.05);2)随着脂肪供能水平的提高,小鼠腹股沟皮下脂肪沉积显著增加(P<0.05),在高脂饮食条件下,Lar-30%组的小鼠腹股沟皮下脂肪组织重量显著高于Rap-30%和Oli-30%组(P<0.05),并且相对于其他两组,Oli-30%组小鼠腹股沟皮下脂肪组织中ROS含量极显著降低(P<0.01);... 相似文献
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Genomic instability in mice lacking histone H2AX 总被引:1,自引:0,他引:1
Celeste A Petersen S Romanienko PJ Fernandez-Capetillo O Chen HT Sedelnikova OA Reina-San-Martin B Coppola V Meffre E Difilippantonio MJ Redon C Pilch DR Olaru A Eckhaus M Camerini-Otero RD Tessarollo L Livak F Manova K Bonner WM Nussenzweig MC Nussenzweig A 《Science (New York, N.Y.)》2002,296(5569):922-927
Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX-/- mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA. 相似文献
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Couse JF Hewitt SC Bunch DO Sar M Walker VR Davis BJ Korach KS 《Science (New York, N.Y.)》1999,286(5448):2328-2331
Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alphabeta estrogen receptor knockout (alphabetaERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alphabetaERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Müllerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary. 相似文献
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Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance 总被引:26,自引:0,他引:26
T Kadowaki C L Bevins A Cama K Ojamaa B Marcus-Samuels H Kadowaki L Beitz C McKeon S I Taylor 《Science (New York, N.Y.)》1988,240(4853):787-790
Insulin receptor complementary DNA has been cloned from an insulin-resistant patient with leprechaunism whose receptors exhibited multiple abnormalities in insulin binding. The patient is a compound heterozygote, having inherited two different mutant alleles of the insulin receptor gene. One allele contains a missense mutation encoding the substitution of glutamic acid for lysine at position 460 in the alpha subunit of the receptor. The second allele has a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit, thereby deleting both the transmembrane and tyrosine kinase domains of the receptor. Interestingly, the father is heterozygous for this nonsense mutation and exhibits a moderate degree of insulin resistance. This raises the possibility that mutations in the insulin receptor gene may account for the insulin resistance in some patients with non-insulin-dependent diabetes mellitus. 相似文献
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Montrasio F Frigg R Glatzel M Klein MA Mackay F Aguzzi A Weissmann C 《Science (New York, N.Y.)》2000,288(5469):1257-1259
In scrapie-infected mice, prions are found associated with splenic but not circulating B and T lymphocytes and in the stroma, which contains follicular dendritic cells (FDCs). Formation and maintenance of mature FDCs require the presence of B cells expressing membrane-bound lymphotoxin-alpha/beta. Treatment of mice with soluble lymphotoxin-beta receptor results in the disappearance of mature FDCs from the spleen. We show that this treatment abolishes splenic prion accumulation and retards neuroinvasion after intraperitoneal scrapie inoculation. These data provide evidence that FDCs are the principal sites for prion replication in the spleen. 相似文献
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It appears that obese animals retain proportionally more steroid hormones than nonobese animals. The retention of these hormones does not appear to be a function of the nature of the obesity syndrome but simply a function of the increased fat content. 相似文献
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Moqrich A Hwang SW Earley TJ Petrus MJ Murray AN Spencer KS Andahazy M Story GM Patapoutian A 《Science (New York, N.Y.)》2005,307(5714):1468-1472
Environmental temperature is thought to be directly sensed by neurons through their projections in the skin. A subset of the mammalian transient receptor potential (TRP) family of ion channels has been implicated in this process. These "thermoTRPs" are activated at distinct temperature thresholds and are typically expressed in sensory neurons. TRPV3 is activated by heat (>33 degrees C) and, unlike most thermoTRPs, is expressed in mouse keratinocytes. We found that TRPV3 null mice have strong deficits in responses to innocuous and noxious heat but not in other sensory modalities; hence, TRPV3 has a specific role in thermosensation. The natural compound camphor, which modulates sensations of warmth in humans, proved to be a specific activator of TRPV3. Camphor activated cultured primary keratinocytes but not sensory neurons, and this activity was abolished in TRPV3 null mice. Therefore, heat-activated receptors in keratinocytes are important for mammalian thermosensation. 相似文献
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Yuan L Liu JG Hoja MR Wilbertz J Nordqvist K Höög C 《Science (New York, N.Y.)》2002,296(5570):1115-1118
Aneuploidy (trisomy or monosomy) is the leading genetic cause of pregnancy loss in humans and results from errors in meiotic chromosome segregation. Here, we show that the absence of synaptonemal complex protein 3 (SCP3) promotes aneuploidy in murine oocytes by inducing defective meiotic chromosome segregation. The abnormal oocyte karyotype is inherited by embryos, which die in utero at an early stage of development. In addition, embryo death in SCP3-deficient females increases with advancing maternal age. We found that SCP3 is required for chiasmata formation and for the structural integrity of meiotic chromosomes, suggesting that altered chromosomal structure triggers nondisjunction. SCP3 is thus linked to inherited aneuploidy in female germ cells and provides a model system for studying age-dependent degeneration in oocytes. 相似文献