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1.
Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.  相似文献   

2.
The mammalian target of rapamycin （mTOR） signaling pathway is evolutionarily conserved, mTOR can integrate and converge a wide range of signals, including intracellular and extracellular nutrients, growth factors, energy and stress conditions, and has a crucial role in the vertebrate growth control. This review analyzed the main components and regulated factors of TOR signaling pathway, explained functions and mechanisms of roTOR during the individual growth, the development and its dynamic role, revealed its additional functions beyond the cell growth control, and finally reviewed the tissue specificity and time specificity of mTOR signaling pathway, and its regulation on sexual differentiation, tissue differentiation and organogenesis in the individual development.  相似文献   

3.
Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.  相似文献   

4.
The fat-derived hormone leptin regulates energy balance in part by modulating the activity of neuropeptide Y and proopiomelanocortin neurons in the hypothalamic arcuate nucleus. To study the intrinsic activity of these neurons and their responses to leptin, we generated mice that express distinct green fluorescent proteins in these two neuronal types. Leptin-deficient (ob/ob) mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto neuropeptide Y and proopiomelanocortin neurons. When leptin was delivered systemically to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects.  相似文献   

5.
The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.  相似文献   

6.
FLCN基因参与多种代谢途径和细胞过程,国内外关于FLCN在奶牛乳腺发育过程中表达及调节的研究鲜有报道。应用RNA干扰技术和质粒转染技术改变FLCN基因在奶牛乳腺上皮细胞中表达量,流式细胞仪检测细胞增殖,采用qRT-PCR和Western blot检测FLCN对泌乳相关功能基因AMPK、mTOR、CyclinD1、Caspase3和β-酪蛋白表达的影响。结果表明,FLCN正向调节mTOR磷酸化水平,促进乳蛋白合成和细胞增殖,抑制细胞凋亡,负调控能量代谢调节子AMPK。FLCN在奶牛乳腺上皮细胞中可通过mTOR信号通路调控细胞增殖及乳蛋白合成,研究对揭示FLCN调控奶牛乳腺上皮细胞增殖和泌乳具有重要作用。  相似文献   

7.
Bai X  Ma D  Liu A  Shen X  Wang QJ  Liu Y  Jiang Y 《Science (New York, N.Y.)》2007,318(5852):977-980
The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate (GTP)-dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.  相似文献   

8.
The obesity epidemic shows no signs of abating. There is an urgent need to push back against the environmental forces that are producing gradual weight gain in the population. Using data from national surveys, we estimate that affecting energy balance by 100 kilocalories per day (by a combination of reductions in energy intake and increases in physical activity) could prevent weight gain in most of the population. This can be achieved by small changes in behavior, such as 15 minutes per day of walking or eating a few less bites at each meal. Having a specific behavioral target for the prevention of weight gain may be key to arresting the obesity epidemic.  相似文献   

9.
为探究罗非鱼高温胁迫响应的调控作用机理,选用孵化12 d后的尼罗罗非鱼Oreochromis niloticus幼鱼,基于RNA-seq技术对尼罗罗非鱼高温处理组(36℃高温胁迫下养殖30、50、70 d)和常温对照组(28℃,30、50、70 d)肝脏组织样品进行转录组分析。结果表明:高温处理组与常温对照组共获得39.23 Gb clean data;28℃-30 d与36℃-30 d文库比较发现,存在4342个差异基因,28℃-50 d与36℃-50 d文库比较发现,存在3139个差异基因,28℃-70 d与36℃-70 d文库比较发现,存在3042个差异基因;进一步将差异表达基因进行GO功能注释和KEGG富集分析,发现差异基因主要富集在糖酵解/糖异生、细胞周期、内质网的蛋白质加工及胰岛素信号等通路上;通过RT-qPCR试验对mTOR信号通路及相关通路中的8个差异基因进行验证,证实了转录组测序结果的可靠性。研究表明,高温胁迫下尼罗罗非鱼肝脏组织中参与热应激相关的基因涉及生长、蛋白质折叠及能量代谢等多个生物学过程,本研究结果为深入研究罗非鱼高温胁迫响应调控机制奠定了基础。  相似文献   

10.
孔雪  宋志刚  焦洪超  林海 《中国农业科学》2010,43(16):3440-3446
【目的】利用皮下注射人工合成糖皮质激素的方式模拟应激,通过核磁共振(NMR)技术研究应激及色氨酸对肉仔鸡下丘脑代谢状况的影响,为探明下丘脑食欲调控机制提供依据。【方法】10日龄AA肉仔鸡32只随机分为4组,早6:00禁食3h后,以2.0mg·kg-1BW剂量皮下注射地塞米松,同时灌注色氨酸(生理盐水溶解,500mg·kg-1BW),对照组分别皮下注射、灌服生理盐水,3h后取血浆及下丘脑。下丘脑用高氯酸萃取后进行核磁共振研究。【结果】通过1HNMR谱,发现应激改变了肉鸡下丘脑乳酸,葡萄糖,ATP,肌醇,3-羟基丁酸的相对含量;未检测到色氨酸信号的改变。【结论】NMR技术能够检测到应激状态下下丘脑代谢物的改变;应激状态下,ATP、葡萄糖和其它能量底物信号的改变可能参与了下丘脑对食欲的调控作用。  相似文献   

11.
Different amino acids have been shown to affect feed intake when injected directly into the central nervous system of birds. In the present study, we investigated the effects of L-glutamine and L-alanine on feed intake and the mRNA expression levels of hypothalamic neuropeptides involved in feed intake regulation in broiler chicks. L-Glutamine or Lalanine was intra-cerebroventricularly (ICV) administered to 4-d-old broiler chicks and the feed intake were recorded at various time points. Quantitative PCR was performed to determine the hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti related protein (AgRP), pro-opiomelanocortin (POMC), melanocortin receptor 4 (MC4R) and corticotropin releasing factor (CRF). Our results showed that ICV administration of L-glutamine (0.55 or 5.5 μmol) significantly increased feed intake up to 2 h post-administration period and the hypothalamic NPY mRNA expression levels, while it markedly decreased hypothalamic POMC and CRF mRNA expression levels. In contrast, ICV administration of L-alanine (4 μmol) significantly decreased feed intake for the first 0.5 h post-administration period, and reduced the hypothalamic AgRP mRNA expression levels, while it remarkablely enhanced the mRNA expression levels of MC4R and CRF. These findings suggested that L-glutamine and L-alanine could act within the hypothalamus to influence feed intake in broiler chicks, and that both orexigenic and anorexigenic neuropeptide genes might contribute directly to these effects.  相似文献   

12.
 【目的】研究初生肉仔鸡血清和下丘脑摄食调节相关激素的发育规律并进行品种间比较。【方法】观测了北京油鸡和AA鸡在孵出后0、1、3、5、7、9和11 d的采食量,血清和下丘脑的胰岛素和瘦素及下丘脑NPY和α-MSH水平的变化。【结果】北京油鸡和AA鸡的生长规律基本一致,但前者的ADFI和ADG极显著低于后者（P＜0.01）。北京油鸡血清胰岛素随日龄的波动较大,而AA鸡除0 d外,其它日龄维持在7.5 μIU•ml-1左右。北京油鸡血清瘦素在各个日龄间无明显差异,而AA鸡1和3 d血清瘦素显著高于0 d（P≤0.03）。北京油鸡下丘脑瘦素随日龄增长呈下降趋势,而AA鸡1 d下丘脑瘦素高于0 d（P＜0.01）,而后有所降低。2个品种的下丘脑胰岛素和NPY随日龄的变化趋势一致。下丘脑胰岛素在出壳后前5 d的水平较高,而后有所下降。下丘脑NPY随日龄增长而上升,其中7 d最高。北京油鸡下丘脑α-MSH在出壳后前7 d的水平较低,而后有所升高,而AA鸡下丘脑α-MSH随日龄增长而降低,达5 d最低,而后又上升。相关分析表明,血清瘦素、下丘脑胰岛素、瘦素和NPY与ADFI的相关性较强,而血清胰岛素和下丘脑α-MSH与ADFI的相关性不强。【结论】血清和下丘脑的摄食相关激素的发育规律因品种和指标不同而异,胰岛素、瘦素、NPY和α-MSH在雏鸡开食过程中可能发挥着一定作用,但其具体调节机制仍需进一步研究。  相似文献   

13.
The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.  相似文献   

14.
肌肉细胞蛋白质合成能力与畜禽产肉量性状有关,试验旨在探究转录因子AT富集区4B(AT-rich interaction domain 4B,ARID4B)对牛磺酸(Taurine,Tau)调节成肌细胞C2C12蛋白质合成的影响.向体外培养C2C12细胞培养液中分别添加0、60、120、180和240μmol·L-1 T...  相似文献   

15.
In addition to digesting and assimilating nutrients, the intestine and associated visceral organs play a key sensing and signaling role in the physiology of energy homeostasis. The gut, the pancreatic islets of Langerhans, elements in the portal vasculature, and even visceral adipose tissue communicate with the controllers of energy balance in the brain by means of neural and endocrine pathways. Signals reflecting energy stores, recent nutritional state, and other parameters are integrated in the central nervous system, particularly in the hypothalamus, to coordinate energy intake and expenditure. Our understanding of regulatory neural circuits and the signaling molecules that influence them has progressed rapidly, particularly after the discovery of the adipocyte hormone leptin. These discoveries have led to exploration of novel routes for obesity control, some of which involve gut-derived pathways.  相似文献   

16.
The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity. Thus, we tested whether striatal activation in response to food intake is related to current and future increases in body mass and whether these relations are moderated by the presence of the A1 allele of the TaqIA restriction fragment length polymorphism, which is associated with dopamine D2 receptor (DRD2) gene binding in the striatum and compromised striatal dopamine signaling. Cross-sectional and prospective data from two functional magnetic resonance imaging studies support these hypotheses, which implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.  相似文献   

17.
The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. Results obtained in vitro and in human cells suggest that amino acid signaling begins within the lysosomal lumen. These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing.  相似文献   

18.
Smoking decreases appetite, and smokers often report that they smoke to control their weight. Understanding the neurobiological mechanisms underlying the anorexic effects of smoking would facilitate the development of novel treatments to help with smoking cessation and to prevent or treat obesity. By using a combination of pharmacological, molecular genetic, electrophysiological, and feeding studies, we found that activation of hypothalamic α3β4 nicotinic acetylcholine receptors leads to activation of pro-opiomelanocortin (POMC) neurons. POMC neurons and subsequent activation of melanocortin 4 receptors were critical for nicotinic-induced decreases in food intake in mice. This study demonstrates that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identifies critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite.  相似文献   

19.
When A1 noradrenergic neurons in the caudal ventrolateral medulla of rabbits are destroyed electrolytically or by local injection of the neurotoxin kainic acid, the concentration of vasopressin in plasma increases, causing hypertension. The A1 neurons may tonically inhibit the activity of vasopressin-secreting neuroendocrine cells through a direct hypothalamic projection.  相似文献   

20.
To detect the mammalian target of rapamycin (mTOR) expressed in Cashmere goat fetal fibroblasts (GFb), mTOR gene was cloned from Inner Mongolia Cashmere goat (Capra hircus) and expressed in Escherichia coli followed by immunizing mice with the purified recombinant protein as an immunogen to produce the anti-goat mTOR recombinant polyclonal antibody. Antiserum was collected from the immunized mice after the fifth immunization and its titer was determined with enzyme-linked immunosorbent assay (ELISA). The results showed that the recombinant polyclonal antibody had a titer 1:200 000 and could react with the mTOR expressed in GFb cells with a specific and sensitive affinity. Western blot showed that mTOR expression and phospho-mTOR (Ser 2448) activity were inhibited when GFb cells were treated with CCI-779, an mTOR specific inhibitor.  相似文献   

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