排序方式: 共有22条查询结果,搜索用时 31 毫秒
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Parton LE Ye CP Coppari R Enriori PJ Choi B Zhang CY Xu C Vianna CR Balthasar N Lee CE Elmquist JK Cowley MA Lowell BB 《Nature》2007,449(7159):228-232
A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes. 相似文献
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A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors 总被引:98,自引:0,他引:98
P Ponte P Gonzalez-DeWhitt J Schilling J Miller D Hsu B Greenberg K Davis W Wallace I Lieberburg F Fuller 《Nature》1988,331(6156):525-527
The amyloid proteins isolated from neuritic plaques and the cerebrovasculature of Alzheimer's disease are self-aggregating moieties termed A4 protein and beta-protein, respectively. A putative A4 amyloid precursor (herein termed A4(695] has been characterized by analysis of a human brain complementary DNA. We report here the sequence of a closely related amyloid cDNA, A4(751), distinguished from A4(695) by the presence of a 168 base-pair (bp) sequence which adds 57 amino acids to, and removes one residue from, the predicted A4(695) protein. The peptide predicted from this insert is very similar to the Kunitz family of serine proteinase inhibitors. The two A4-specific messenger RNAs are differentially expressed: in a limited survey, A4(751) mRNA appears to be ubiquitous, whereas A4(695) mRNA has a restricted pattern of expression which includes cells from neuronal tissue. These data may have significant implications for understanding amyloid deposition in Alzheimer's disease. 相似文献
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Understanding the relative timings of climate events in the Northern and Southern hemispheres is a prerequisite for determining the causes of abrupt climate changes. But climate records from the Patagonian Andes and New Zealand for the period of transition from glacial to interglacial conditions--about 14.6-10 kyr before present, as determined by radiocarbon dating--show varying degrees of correlation with similar records from the Northern Hemisphere. It is necessary to resolve these apparent discrepancies in order to be able to assess the relative roles of Northern Hemisphere ice sheets and oceanic, atmospheric and astronomical influences in initiating climate change in the late-glacial period. Here we report pollen records from three sites in the Lake District of southern Chile (41 degrees S) from which we infer conditions similar to modern climate between about 13 and 12.2 14C kyr before present (BP), followed by cooling events at about 12.2 and 11.4 14C kyr BP, and then by a warming at about 9.8 14C kyr BP. These events were nearly synchronous with important palaeoclimate changes recorded in the North Atlantic region, supporting the idea that interhemispheric linkage through the atmosphere was the primary control on climate during the last deglaciation. In other regions of the Southern Hemisphere, where climate events are not in phase with those in the Northern Hemisphere, local oceanic influences may have counteracted the effects that propagated through the atmosphere. 相似文献
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Towards a molecular understanding of adaptive thermogenesis 总被引:50,自引:0,他引:50
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Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error), but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We 'tagged' dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error. 相似文献
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Decline of surface temperature and salinity in the western tropical Pacific Ocean in the Holocene epoch 总被引:1,自引:0,他引:1
In the present-day climate, surface water salinities are low in the western tropical Pacific Ocean and increase towards the eastern part of the basin. The salinity of surface waters in the tropical Pacific Ocean is thought to be controlled by a combination of atmospheric convection, precipitation, evaporation and ocean dynamics, and on interannual timescales significant variability is associated with the El Ni?o/Southern Oscillation cycles. However, little is known about the variability of the coupled ocean-atmosphere system on timescales of centuries to millennia. Here we combine oxygen isotope and Mg/Ca data from foraminifers retrieved from three sediment cores in the western tropical Pacific Ocean to reconstruct Holocene sea surface temperatures and salinities in the region. We find a decrease in sea surface temperatures of approximately 0.5 degrees C over the past 10,000 yr, whereas sea surface salinities decreased by approximately 1.5 practical salinity units. Our data imply either that the Pacific basin as a whole has become progressively less salty or that the present salinity gradient along the Equator has developed relatively recently. 相似文献
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BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis 总被引:1,自引:0,他引:1
Danial NN Gramm CF Scorrano L Zhang CY Krauss S Ranger AM Datta SR Greenberg ME Licklider LJ Lowell BB Gygi SP Korsmeyer SJ 《Nature》2003,424(6951):952-956
Glycolysis and apoptosis are considered major but independent pathways that are critical for cell survival. The activity of BAD, a pro-apoptotic BCL-2 family member, is regulated by phosphorylation in response to growth/survival factors. Here we undertook a proteomic analysis to assess whether BAD might also participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A and protein phosphatase 1 (PP1) catalytic units, Wiskott-Aldrich family member WAVE-1 as an A kinase anchoring protein, and glucokinase (hexokinase IV). BAD is required to assemble the complex in that Bad-deficient hepatocytes lack this complex, resulting in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient for BAD or bearing a non-phosphorylatable BAD(3SA) mutant display abnormal glucose homeostasis including profound defects in glucose tolerance. This combination of proteomics, genetics and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis. 相似文献