| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Function of a STIM1 homologue in C. elegans: evidence that store-operated Ca2+ entry is not essential for oscillatory Ca2+ signaling and ER Ca2+ homeostasis.
Yan X, Xing J, Lorin-Nebel C, Estevez AY, Nehrke K, Lamitina T, and Strange K. J Gen Physiol 128: 443–459, 2006.
Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu
Question: Is store-operated Ca2+ entry (SOCE) necessary for oscillatory Ca2+ signaling or Ca2+ homeostasis in the endoplasmic reticulum (ER)?
Background: Changes in cytoplasmic Ca2+ levels occur either from an influx of Ca2+ across the plasma membrane or release of Ca2+ from intracellular stores. The ER is a major source of intracellular Ca2+ release, which is mediated by 1,4,5-trisphosphate (IP3) receptor Ca2+ channels. When intracellular Ca2+ stores are depleted, Ca2+ influx across the plasma membrane is stimulated, a process known as SOCE. SOCE is hypothesized to be essential for regulating calcium homeostasis in the cell; however, few in vivo studies of the pathway’s significance have been carried out.
Observations: Yan et al. examined the role of SOCE in IP3 and oscillatory Ca2+ signaling pathways in Caenorhabditis elegans by inhibiting stromal interaction molecule 1 (STIM1), which was recently identified as the ER Ca2+ sensor that regulates SOCE. The results showed, surprisingly, that some calcium-dependent behaviors were normal in animals lacking STIM1.
Significance: These results suggest that SOCE is not essential for certain oscillatory Ca2+ signaling processes or for the maintenance of Ca2+ stores in C. elegans. Thus SOCE appears to be either redundant with other processes or is playing specialized roles in Ca2+ homeostasis. Nonetheless, introducing the use of C. elegans to study SOCE opens the possibility of genetically dissecting this process and can help reveal its complexities in vivo under normal and pathophysiological conditions.
Graded regulation of the Kv2.1 potassium channel by variable phosphorylation.
Park KS, Mohapatra DP, Misonou H, and Trimmer JS. Science 313: 976–979, 2006.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: How are graded functional changes of the voltage-gated potassium (KV) channel KV2.1 achieved?
Background: KV channels provide outward currents to repolarize a cell following an action potential. Although the KV2.1 channel is ubiquitous in the nervous system, it does not appear to contribute to repolarization of single action potentials because it has a high threshold for activation and slow activation kinetics. Instead, multiple phosphorylation sites allow KV2.1 to act as a rheostat, a resistor that regulates neuronal firing. KV2.1 is highly phosphorylated in resting neurons and dephosphorylated by calcineurin on excitatory synaptic activity, which leads to graded enhancement of KV2.1 activity by lowering its activation threshold and accelerating its activation kinetics. However, the identification of the KV2.1 phosphorylation sites involved in these graded changes has been difficult because of the large number of phosphorylation sites that have been predicted.
Observations: Park et al. combined mass spectrometry-based proteomics and ion channel biophysics to identify the phosphorylation sites on KV2.1. Sixteen phosphorylation sites were identified, seven of which were sensitive to calcineurin dephosphorylation. Mutations of individual calcineurin-regulated phosphorylation sites revealed a complex regulation of KV2.1. As expected, phosphorylation at various sites of the channel resulted in graded changes of channel gating and ionic currents.
Significance: These data suggest that KV2.1 possesses a homeostatic plasticity that allows it to exist in a number of different functional states to maintain an optimal cellular environment in response to signals from various sources. The molecular underpinning of this regulatory mechanism appears to result from phosphorylation at 16 sites. It is conceivable that dysfunction of this graded regulatory mechanism may be associated with various pathological conditions, such as epileptic seizures. Thus therapeutic interventions could potentially be developed to modulate KV2.1 phosphorylation and treat neurological and psychiatric disorders.
Multiple phosphorylation sites confer reproducibility of the rod’s single-photon responses.
Doan T, Mendez A, Detwiler PB, Chen J, and Rieke F. Science 313: 530–533, 2006.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: Do the multiple phosphorylation sites of rhodopsin underlie the highly reproducible single photon responses of rods?
Background: The retina receives light through photoreceptors: rods and cones. Rod are exquisitely sensitive to dim light, whereas cones operate at higher light levels and provide the signals on which color vision is based. Within rods, a single photon of light activates rhodopsin, the G-protein-coupled receptor responsible for the initiation of the electrical response. This electrical response is unlike other responses induced by single molecules in that it is highly reproducible; i.e., the amplitude and duration of rhodopsin activity is highly consistent. Previous research suggests that the low variability in the response of rods is due to the deactivation of the rhodopsin sensor through several phosphorylation steps.
Observations: To determine whether multiple phosphorylations of rhodopsin provide steps that reduce variability in rhodopsin shutoff, Doan et al. measured the current responses to single rhodopsin activations. They did, in fact, find that each phosphorylation site of rhodopsin contributed to its deactivation and that, collectively, these phosphorylation sites controlled the activity of rhodopsin. Furthermore, they found that mutating any phosphorylation site, regardless of which site was mutated, equally increased the variability of the response to a single photon.
Significance: These results suggest that the consistency in the amplitude and duration of rods’ single-photon responses results from multiple phosphorylation sites of rhodopsin that provide independent deactivation signals. A multistep shutoff model is further supported by the finding that each phosphorylation site contributes an equal amount to the regulation of rhodopsin. It will be interesting to see whether other G-protein-coupled receptors are revealed that use a similar regulatory mechanism.
Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism.
Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K, and Pos KM. Science 313: 1295–1298, 2006.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: What is the mechanism by which the AcrB pump mediates the efflux of molecules from gram-negative bacteria?
Background: Although all bacteria have an inner cell membrane, gram-negative bacteria have the distinction of a double membrane surrounding each bacterial cell. This outer membrane excludes certain drugs and antibiotics from penetrating the cell, which is in part why gram-negative bacteria are generally more resistant to antibiotics than gram-positive bacteria. Resistance-nodulation-division (RND) efflux systems are membrane proteins responsible for pumping drugs out of gram-negative bacteria via a proton motive force. Although a previous symmetric structure of the trimeric RND pump, AcrB, has been described, the mechanism of solute transport has not been clearly defined due to a lack of structural data.
Observations: Seeger et al. determined a new asymmetric structure of the AcrB pump that has three distinct monomer conformations, which represent the progressive stages of its transport cycle. During cycling, a tunnel inside the monomer allows the antibiotic substrate to be transported from the cell toward the outside. In the first step, the "loose" monomer binds a substrate in its transmembrane domain. The substrate is then transported to a hydrophobic binding pocket when the monomer is converted to the "tight" conformation. Finally, the substrate is released when the monomer is converted to the "open" conformation.
Significance: The model proposed here suggests that the physiologically relevant form of the AcrB pump is an asymmetric trimer that undergoes a functional rotation and creates a peristaltic pump mechanism in each monomer to pump molecules out into extracellular space. Because RND pumps appear to be involved in drug resistance, especially in gram-negative bacteria, the characterization of these efflux pumps is essential for the development of effective therapies to improve control of infectious diseases.
Ultrafine mapping of Dyscalc1 to an 80 Kb chromosomal segment on chromosome 7 in mice susceptible for dystrophic calcification. Aherrahrou Z, Doehring LC, Kaczmarek PM, Liptau H, Ehlers EM, Pomarino A, Wrobel S, Gotz A, Mayer B, Erdmann J, and Schunkert H. Physiol Genomics (August 22, 2006); doi: 10.1152/physiolgenomics.00133.2006.
Nominated by Allen Cowley
Editor, Physiological Genomics
Medical College of Wisconsin
cowley{at}mcw.edu
Question: Is the ATP-binding cassette C6 (Abcc6) the dystrophic cardiovascular calcifications (DCC) gene?
Background: DCC are markers of atherosclerosis and a number of clinically significant complications, including myocardial ischemia, myocardial infarction, congestive heart failure, and cardiac arrhythmias. The genetic causes of cardiovascular calcifications have been explored in mouse models of DCC and have identified a major locus named Dyscalc 1 on mouse chromosome 7 as a contributor to myocardial and vascular calcification. Recent work suggests that Abcc6 is a candidate gene for DCC.
Observations: Aherrahrou et al. took advantage of the differential occurrence of the DCC phenotype in fifteen mouse strains. Linking the phenotype with the genotype information allowed an in silico (computer assisted) segregation analysis to be performed. Within a 1 million base pairs locus of Dyscalc 1, 51 genes were studied with respect to mRNA expression in response to injury. Five differentially expressed genes were identified, from which seven novel SNPs were genotyped. This revealed an 80-Kb region as the locus of Dyscalc 1 that contains three genes, EMP-3, BC013491, and Abcc6 (3' of rs3703247 SNP marker). The authors favor EMP-3 as a candidate gene for DCC and not Abcc6.
Significance: By utilizing a novel strategy to test only a small number of genes, as opposed to the few hundred left to study by traditional approaches, this work narrows the locus for DCC on mouse chromosome 7 to an 80-Kb segment containing only three genes. The results are of interest both physiologically and from a clinical perspective since dystrophic calcification is an important feature of several vascular pathologies.
Mechanisms underlying myosin heavy chain expression during development of the rat diaphragm muscle. Geiger PC, Bailey JP, Mantilla CB, Zhan WZ, and Sieck GC. J Appl Physiol (July 27, 2006); doi:10.1152/japplphysiol.00221.2006.
Nominated by Jerry Dempsey
Editor, Journal of Applied Physiology
University of Wisconsin
jdempsey{at}wisc.edu
Question: Do changes in the transcription of myosin heavy chain (MHC) isoforms control the changes that occur in the protein expression of MHC?
Background: Myosins are the motor proteins responsible for actin-based motility. The heavy chains of myosin have a globular motor domain, which catalyzes ATP hydrolysis and interacts with actin, and a tail domain, which promotes dimerization with other heavy chains. During the first 4 weeks of postnatal development in the rat diaphragm muscle (DIAm), there are significant changes in MHC isoform expression, which is associated with increased MHC protein expression and fiber growth. Geiger et al. hypothesized that the postnatal changes in MHC isoform mRNA expression lead to a concomitant change in the expression of MHC protein.
Observations: MHC mRNA and MHC protein expression was determined in rat DIAm at several postnatal time points. Both MHC isoform mRNA and protein expression were affected by the postnatal age of the sample. Protein and mRNA levels of the MHCNeo isoform increased until postnatal day 14 and then decreased by day 28. In contrast, changes in mRNA expression of the MHCSlow and MHC2X isoforms were small, while changes in their protein expression increased significantly.
Significance: These results suggest that some, but not all, of the changes that occur postnatally in the protein expression of MHC are driven by transcriptional changes. Therefore, simply knowing the levels of mRNA of a specific MHC isoform will not necessarily dictate the level of protein expressed. This, and other studies, suggest a complex regulatory mechanism that controls postnatal MHC isoform expression in the rat DIAm.
Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance.
Gibala MJ, Little JP, van Essen M, Wilkin GP, Burgomaster KA, Safdar A, Raha S, and Tarnopolsky MA. J Physiol 575: 901–911, 2006.
Nominated by Paul Greenhaff
University of Nottingham
Paul.greenhaff{at}nottingham.ac.uk
Question: Does short-term high-intensity training induce metabolic and performance adaptations comparable to those induced by endurance training?
Background: The overload principle posits that, when the body is subjected to unaccustomed stress, it adapts physiologically so that it is better prepared for a subsequent stress event. The specificity principle posits that the adaptive response is specific to the type of stimulus imposed. However, whether sprint-interval training (SIT) induces adaptations that are similar to those induced by traditional endurance training (ET) has only recently been explored in laboratory exercise research. In a previous study, Gibala and colleagues found that SIT increased levels of key markers of aerobic metabolic activity and time to exhaustion at 80% VO2 peak power output in untrained subjects. However, a limitation of this study was that it compared one group who did the SIT and another group who did no exercise.
Observations: In this report, Gibala et al. compared the efficacy of a 2-wk SIT style of training (4–6 times 30-s bursts of all-out cycling, separated by 4 min of recovery, per session) with an ET program (90–120 min of continuous moderate-intensity cycling per session). Notably, in this study, they altered the style of performance testing from exercise at set intensity to exhaustion in their previous study to a time trial-based exercise where subjects were told to complete work as quickly as possible, which more closely simulates normal athletic competition (i.e., a race). Both groups showed similar improvements in exercise performance, muscle glycogen storage capacity, muscle buffering capacity, and aerobic enzymes.
Significance: The authors thus showed that short bursts of very intense exercise, equivalent to only a few minutes per day, stimulated adaptations that mimicked traditional endurance training, at least in young active men. Although these findings may not change the training paradigms of elite athletes, they may have important implications for those wishing to maintain fitness, and they also provide clues to the complex nature of the response to endurance exercise.
Learning induces long-term potentiation in the hippocampus.
Whitlock JR, Heynen AJ, Shuler MG, and Bear MF. Science 313: 1093–1097, 2006.
Nominated by Julie Kauer
Brown University
julie_kauer{at}brown.edu
Question: Does inhibitory avoidance learning induce long-term potentiation (LTP)?
Background: It has been repeatedly demonstrated that LTP, which is a long-lasting enhancement in synaptic efficacy, can be induced in hippocampal slices through high-frequency stimulation (HFS) and that blocking LTP impairs spatial learning in animals. In the CA1 region of the hippocampus, there is evidence that HFS-induced LTP results primarily from NMDA-dependent phosphorylation and trafficking of AMPA receptors, which leads to an increase in the number and single-channel conductance of AMPA receptors at the postsynaptic surface. This, and other evidence, has led to the hypothesis that LTP underlies memory formation in the hippocampus. However, despite the abundance of circumstantial evidence, it has been never directly demonstrated that LTP is induced by learning.
Observations: Using the inhibitory avoidance (IA) paradigm, which, in a single session, trains rats to avoid one side of a chamber by administering a mild food shock, Whitlock et al. found an NMDA-dependent increase in the phosphorylation of the same amino acid in AMPA receptors that occurs following HFS. This was accompanied by an increase in the number of AMPA receptors at the synapse. In addition, by using a multi-electrode array, they found that IA induced a spatially selective increase in the amplitude of evoked excitatory transmission, which occluded HFS-induced LTP.
Significance: Proving that LTP underlies learning has been the primary focus of numerous laboratories since it was first reported by Bliss and Lomo. Not only does this study provide the first direct evidence that hippocampal-dependent learning induces LTP at synapses, it also challenges other widely held views concerning LTP. Most notably, the current results suggest that memory is concentrated in cell subpopulations and not uniformly distributed across the hippocampus.
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16(INK4a). Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, Depinho RA, Sharpless NE, and Scadden DT. Nature 443: 421–426, 2006.[Medline]
Increasing p16(INK4a) expression decreases forebrain progenitors and neurogenesis during ageing. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, and Morrison SJ. Nature 443: 448–452, 2006.[CrossRef][Medline]
p16(INK4a) induces an age-dependent decline in islet regenerative potential. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, and Sharpless NE. Nature 443: 453–457, 2006.[CrossRef][Medline]
Nominated by Jose Lopez-Barneo
Laboratorio de Investigaciones Biomedicas
jose.l.barneo.sspa{at}juntadeandalucia.es
Question: What mediates the gradual loss of the ability of stem cells to divide and generate new cells as they age?
Background: Stem cells are undifferentiated, primitive cells that can multiply and differentiate into specific kinds of cells to repair or regenerate damaged tissues. However, if not, regulated cells may hyper-proliferate and cause disease. Stem cell proliferation is therefore regulated by tumor-suppressing proteins, such as the cyclin-dependent kinase inhibitor (p16INK4a), which permanently halts the cell division cycle (senescence). Interestingly, as animals age, stem cell function declines, and p16INK4a expression increases. Thus it has been hypothesized that p16INK4a may cause the age-dependent decline in stem cell function.
Observations: Three separate reports suggest that p16INK4a regulates ageing in stem cells. In the first report, Janzen et al. found that p16INK4a accumulates in mouse haematopoietic stem cells (HSC) as they age and that p16INK4a modulates specific age-associated functions of HSC. In fact, when p16INK4a was absent, there was an increase in the number and function of HSC and a decrease in apoptosis. In the second manuscript, Molofsky et al. also found that p16INK4a accumulates while stem cell number and function declined with age in the mouse brain. Similar to Janzen et al., when p16INK4a was absent, stem cell function and neuronal production were enhanced in old mice compared with wild-type mice. This effect was region specific; the p16INK4a deficiency did not mitigate the age-related atrophy normally seen in the cortex or the loss of function associated with the hippocampus. Finally, Krishnamurthy et al. determined that p16INK4a increases with age in pancreatic islet cells. Mice that were deficient in p16INK4a had increased proliferation and function of islet cells. However, when p16INK4a was overexpressed, islet cells stopped dividing earlier than in wild-type mice.
Significance: Previously, p16INK4a was thought to be an important gene for inhibiting cancer formation by inducing senescence in stem cells. However, these reports suggest p16INK4a has a role under normal physiological conditions: it mediates the gradual loss of the ability of stem cells to proliferate as they age. This suggests that attenuating p16INK4a expression in specific tissues could lead to new treatments for a number of diseases, such as diabetes. Although it is exciting to think about the potential of developing therapies to slow the ageing process, it is important to keep in mind that manipulating p16INK4a function could increase the risk of developing cancer.
E3-targeted anti-TRPC5 antibody inhibits store-operated calciumentry in freshly-isolated pial arterioles. Xu SZ, Boulay G, Flemming R, and Beech DJ. Am J Physiol Heart Circ Physiol (July 21, 2006); doi:10.1152/ajpheart.00495.2006.
Nominated by Alberto Nasjletti
Editor, American Journal of Physiology—Heart and Circulatory Physiology
New York Medical College
alberto_nasjletti{at}nymc.edu
Question: Do the canonical transient receptor potential 1 (TRPC1) and TRPC5 contribute to Ca2+ entry in response to store depletion in arteriole smooth muscle cells?
Background: Arterioles are small-diameter blood vessels with thin muscular walls that branch out from arteries and lead to capillaries. The smooth muscle cells have voltage-gated Ca2+ channels as well as an unidentified store-operated channel (SOC), which opens in response to depletion of Ca2+ stores. Classical transient receptor potential (TRPC) genes have been suggested to encode SOCs, and TRPC1 is expressed in arteriolar smooth muscle. However, recent studies suggest that TRPC1 does not function alone.
Observations: Xu et al. hypothesized that TRPC1 does not function alone in arteriolar Ca2+ signaling; rather, it is enabled by TRPC5. Employing E3-targeting, which uses isoform-specific antibodies, they made an anti-TRPC5 blocking agent (T5E3) to characterize store-operated Ca2+ entry in arterioles. T5E3 suppressed Ca2+ entry in store-depleted arterioles but was without effect when arterioles were not depleted of Ca2+ stores. In contrast T5E3 had no effect on TRPC6, a related protein strongly linked to vascular smooth muscle function.
Significance: These data suggest that TRPC1 and TRPC5 are essential for Ca2+ entry in response to store depletion in smooth muscle cells of arterioles. As the molecular components of SOCs are elucidated, further insight into the physiological roles of these channels in arterioles should result. This work also highlights the power of pharmacological antibodies as tools in discovering the molecular identity of novel channels and their potential use for therapeutic purposes.
Single Cl–channels activated by Ca2+ in Drosophila s2 cells are mediated by bestrophins.
Chien LT, Zhang ZR, and Hartzell HC. J Gen Physiol 128: 247–259, 2006.
Nominated by Larry Palmer
Associate Editor, Journal of General Physiology
Cornell University
lgpalm{at}med.cornell.edu
Question: Does the plasma membrane protein bestrophin function as a Cl– channel under physiological conditions?
Background: Best vitelliform macular dystrophy (BVMD) is a form of macular degeneration that is associated with an abnormality in the human bestrophin-1 (VMD2) gene. Although the underlying mechanism is unknown, several lines of evidence suggest that a defective Cl– channel underlies BVMD. Likewise, there is evidence that bestrophin-1, which is expressed in the basolateral membrane of the retinal pigment epithelium, is the defective Cl– channel. However, bestrophin currents have not been described in any native cells, only in overexpression systems.
Observations: Chien et al. sought to determine whether bestrophins function as Ca2+-actived Cl– (CaC) channels under normal physiological conditions. They found that the Drosophila S2 cell line expresses four bestrophins (dbest1–4) and has an endogenous CaC current. Using interfering RNA, they concluded that the endogenous S2 CaC currents were mediated by bestrophins, which were primarily produced by dbest1 and dbest2 subunits. Further experiments verified that the CaC currents were mediated by bestrophins and delineated their single-channel properties.
Significance: This research should settle much of the debate concerning whether bestrophins are native CaC channels. Clearly, this work has implications for understanding the role Cl– channel dysfunction has in macular degeneration. However, Cl– channels are essential for a myriad of physiological functions. Thus these results may also be important for understanding other diseases that are associated with defects in Cl– channels such as cystic fibrosis, myotonias, osteopetrosis, deafness, kidney disorders, and neurodegenerative diseases.
Regulation of CRAC channel activity by recruitment of silent channels to a high open-probability gating mode.
Prakriya M and Lewis RS. J Gen Physiol 128: 373–386, 2006.
Nominated by Larry Palmer
Associate Editor, Journal of General Physiology
Cornell University
lgpalm{at}med.cornell.edu
Question: What are the permeation and gating properties of Ca2+ release-activated Ca2+ (CRAC) channels?
Background: Changes in cytoplasmic Ca2+ levels occur either from an influx of Ca2+ across the plasma membrane or release of Ca2+ from intracellular stores. When intracellular stores of Ca2+ are depleted, Ca2+ enters across the plasma membrane and causes a Ca2+ release-activated Ca2+ current (ICRAC). CRAC channels are highly selective for Ca2+ over monovalent cations, but monovalent cations permeate the channel in the absence of Ca2+. Moreover, CRAC channels have a conductance 100 times smaller than most other Ca2+ channels, which has made it difficult to elucidate permeation and gating properties of the channel.
Observations: Prakriya and Lewis first determined the size of the CRAC channel pore by measuring permeability ratios for a series of monovalent cations of varying diameter. Next they characterized the Ca2+-dependent block of monovalent cations. Then they introduced an improved use of non-stationary to estimate single channel conductance of CRAC channels; values were threefold higher than previous estimates. This approach also suggests an open probability that is much larger than previously predicted.
Significance: These results demand a revision of previous estimates of CRAC channel pore size, unitary conductance, and open probability, which further distinguish CRAC channels form other Ca2+ channels. This is an important issue, since good measurements will be crucial to the eventual molecular identification of the CRAC channel. The long-term goal of these studies is to understand the physiological functions of these channels in T-cell activation and granule release, and their dysregulation in disease states, as they are implicated in a hereditary severe combined immune deficiency syndrome and the etiology of Alzheimer’s disease.
Sympathetic, but not sensory denervation stimulates white adipocyte proliferation. Foster MT and Bartness TJ. Am J Physiol Regul Integr Comp Physiol (August 3, 2006); doi:10.1152/ajpregu.00197.2006.
Nominated by Pontus Persson
Editor, Americal Journal of Physiology—Regulatory, Integrative and Comparative Physiology
Humboldt University
pontus.persson{at}charite.de
Question: What role, if any, do the sympathetic and sensory nervous systems play in adipocyte proliferation?
Background: Obesity increases the risk of many diseases and health conditions, including hypertension, dyslipidemia, diabetes, heart disease, and stroke, to name a few. A hallmark of obesity is a large number of fat cells. Thus when energy intake exceeds energy expended, new adipocytes form. White adipose tissue (WAT) is innervated by both the sensory and sympathetic nervous systems, and the authors previously demonstrated that surgical denervation of WAT triggers an apparent increase in fat cell number. However, it is unknown whether there was a true increase in fat cells or simply a filling of existing fat cells and, in either case, whether this was due to sympathetic or sensory innervation of WAT.
Observations: Foster and Bartness surgically denervated inguinal WAT (IWAT) in hamsters, which induced adipocyte proliferation. Similarly, when IWAT was selectively denervated of sympathetic inputs, there was an increase in adipocytes. In contrast, when IWAT was selectively denervated of sensory inputs, there was no change in adipocytes.
Significance: These data indicate that surgical denervation does in fact induce adipocyte proliferation rather than causing existing adipocytes to fill. Moreover, this manuscript provides the first direct evidence that sympathetic nerves inhibit white adipocyte proliferation in vivo. This information should help to further elucidate the neural control of energy balance and its potential role in pathological conditions of energy balance, such as obesity.
Quantitative trait loci for carbohydrate and total energy intake on mouse chromosome 17: congenic strain confirmation and candidate gene analyses (Glo1, Glp1r). Kumar KG, Poole AC, York B, Volaufova J, Zuberi A, and Smith Richards BK. Am J Physiol Regul Integr Comp Physiol (August 31, 2006); doi:10.1152/ajpregu.00491.2006.
Nominated by Pontus Persson
Editor, American Journal of Physiology—Regulatory, Integrative and Comparative Physiology
Humboldt University
pontus.persson{at}charite.de
Question: Can a congenic strain verify a complex genetic locus on mouse chromosome 17 to which quantitative traits (QTL) for nutrient intake have been mapped? Do changes in sequence and expression of positional genes with relevant function (Glp1r and Glo1) establish these genes as candidates that influence the phenotypic trait expression?
Background: Quantitative traits are controlled by multiple genes and have a continuous distribution of values. A previous study in this laboratory demonstrated continuous variation in preferential fat consumption across 13 mouse inbred strains, ranging from 26 to 83% of total energy. Subsequently, an intercross of two strains noted for their high fat (C57BL/6J) and carbohydrate (CAST/Ei) intake was used to identify the first genetic linkage for dietary carbohydrate, fat, and total calorie intake, including a region on proximal chromosome 17 that colocalized with significant QTL for increased macronutrient intake-carbohydrate (Mnic1) and total kilocalorie intake (Kcal2).
Observations: To isolate and confirm this chromosome 17 QTL, a congenic strain was developed in which CAST donor segment approximating the QTL region was introgressed onto the B6 genome. The B6.CAST-17 congenic strain ate significantly more carbohydrate and total calories per body weight than the B6 strain, thus verifying the genetic linkage for these traits. Two genes located within the congenic segment, with apparent relevance to food intake, gastric emptying (glucagon-like peptide 1 receptor, Glp1r), and carbohydrate metabolism (glyoxalase I, Glo1) were investigated. Results of sequence analyses and expression profiling support these as strong candidates for the QTL genes in this model.
Significance: Adding to their previous research, which mapped the first mammalian QTL for nutrient intake, Smith Richards and colleagues have now shown that a chromosome 17 locus linked to carbohydrate and total energy consumption retains its effect in congenic mice. This new strain model provides a powerful tool for the identification and eventual positional cloning of genes and pathways controlling macronutrient and total energy intake in the mouse. Finding the genes/transcripts regulating nutrient intake in mice will help us to understand nutrient selection in humans and could lead to valuable insights into obesity.
| ||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
