Christopher J Rhodes

University of Chicago, Chicago, IL, United States

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Publications (116)817.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing cell types that comprise a major autonomic output nucleus and play critical roles in the control of food intake and energy homeostasis. The roles of specific PVH neuronal subtypes in energy balance have yet to be defined, however. The PVH contains nitric oxide synthase-1 (Nos1)-expressing (Nos1(PVH)) neurons of unknown function; these represent a subset of the larger population of Sim1-expressing PVH (Sim1(PVH)) neurons. To determine the role of Nos1(PVH) neurons in energy balance, we used Cre-dependent viral vectors to both map their efferent projections and test their functional output in mice. Here we show that Nos1(PVH) neurons project to hindbrain and spinal cord regions important for food intake and energy expenditure control. Moreover, pharmacogenetic activation of Nos1(PVH) neurons suppresses feeding to a similar extent as Sim1(PVH) neurons, and increases energy expenditure and activity. Furthermore, we found that oxytocin-expressing PVH neurons (OXT(PVH)) are a subset of Nos1(PVH) neurons. OXT(PVH) cells project to preganglionic, sympathetic neurons in the thoracic spinal cord and increase energy expenditure upon activation, though not to the same extent as Nos1(PVH) neurons; their activation fails to alter feeding, however. Thus, Nos1(PVH) neurons promote negative energy balance through changes in feeding and energy expenditure, whereas OXT(PVH) neurons regulate energy expenditure alone, suggesting a crucial role for non-OXT Nos1(PVH) neurons in feeding regulation.
    The Journal of neuroscience : the official journal of the Society for Neuroscience. 11/2014; 34(46):15306-18.
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    ABSTRACT: Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates neurons of the parabrachial nucleus (PBN) that coexpress leptin receptor (LepRb) and cholecystokinin (CCK) (PBN LepRb(CCK) neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, whereas their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.
    Nature neuroscience. 11/2014;
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    ABSTRACT: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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    Christopher J Rhodes, Morris F White, John L Leahy, Steven E Kahn
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    ABSTRACT: In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic β-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1-3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse studies, and some human investigations would be supportive of the notion, there exist different insights, other studies, and circumstantial evidence that question the concept. Therefore, the idea of autocrine action of insulin remains a conundrum. Here we outline a series of thoughts, insights, and alternative interpretations of the available experimental evidence. We ask, how convincing are these, and what are the confusing issues? We agree that there is a clear contribution of certain downstream elements in the insulin signaling pathway for β-cell function and survival, but the question of whether insulin itself is actually the physiologically relevant ligand that triggers this signal transduction remains unsettled.
    Diabetes 07/2013; 62(7):2157-2163. · 7.90 Impact Factor
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    ABSTRACT: Neurons of the lateral hypothalamic area (LHA) control motivated behaviors such as feeding and ambulatory activity, in part by modulating mesolimbic dopamine (DA) circuits. The hormone, leptin, acts via the long form of the leptin receptor (LepRb) in the brain to signal the repletion of body energy stores, thereby decreasing feeding and promoting activity. LHA LepRb neurons, most of which contain neurotensin (Nts; LepRb(Nts) neurons) link leptin action to the control of mesolimbic DA function and energy balance. To understand potential roles for Nts in these processes, we examined mice null for Nts receptor 1 (NtsR1KO). While NtsR1KO mice consume less food than controls on a chow diet, they eat more and become obese when fed a high-fat, high-sucrose palatable diet; NtsR1KO mice also exhibit augmented sucrose preference, consistent with increased hedonic feeding in these animals. We thus sought to understand potential roles for NtsR1 in the control of the mesolimbic DA system and LHA leptin action. LHA Nts cells project to DA-containing midbrain areas, including the ventral tegmental area (VTA) and the substantia nigra (SN), where many DA neurons express NtsR1. Furthermore, in contrast to wild-type mice, intra-LHA leptin treatment increased feeding and decreased VTA Th expression in NtsR1KO mice, consistent with a role for NtsR1 signaling from LHA LepRb neurons in the suppression of food intake and control of mesolimbic DA function. Additionally, these data suggest that other leptin-regulated LHA neurotransmitters normally oppose aspects of Nts action to promote balanced responses to leptin.
    Molecular metabolism. 01/2013; 2(4):423-434.
  • Wilfredo Rosario, Christopher Rhodes, Martin Myers
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    ABSTRACT: For over 150 years it has been known that certain brain injuries perturb metabolism. Within the last 30 years it has been known that there is a degree of neuronal control of insulin and glucagon secretion in response to nutrients, hormones and incretins. However, the precise neuronal pathway involved in regulating these pancreatic secretions remains largely unknown. In this study, we unveil a map of the brain that traces this pathway and indicates which parts of the brain connect to pancreatic islets, likely involved in regulating their function. We infected the pancreas of mice with a retrograde neuronal tracer, an attenuated pseudorabies virus expressing the LacZ gene reporter (PRV-BaBlu) and then probed brain beta-galactosidase detection at 24, 48, 72, and 96 hours. This enabled us to detect specific areas reached by the virus via autonomic nervous system from the pancreas. Viral tracing ends in the hypothalamus at the longest time point, indicating a major link of the hypothalamus to the endocrine pancreas. Very little PRV-BaBlu could be traced to other areas of the CNS. A characterization of this viral map co-localizes hypothalamic glucokinase to PRV-BaBlu positive neurons, indicating this tracing map overlaps with metabolic homeostasis control centers. In summary, we have generated the first map of the CNS link to the endocrine pancreas, directed to the hypothalamus, a central regulator of metabolic homeostasis and, now, also likely of endocrine pancreas physiology. Having this map will enable ongoing studies to establish the functional significance of hypothalamic control of pancreatic islet function.
    2012 Society for Advancement of Hispanics/Chicanos and Native Americans in Science National Conference; 10/2012
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    Peter Arvan, Massimo Pietropaolo, David Ostrov, Christopher J Rhodes
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    ABSTRACT: Islet autoantigens associated with autoimmune type 1 diabetes (T1D) are expressed in pancreatic β cells, although many show wider patterns of expression in the neuroendocrine system. Within pancreatic β cells, every T1D autoantigen is in one way or another linked to the secretory pathway. Together, these autoantigens play diverse roles in glucose regulation, metabolism of biogenic amines, as well as the regulation, formation, and packaging of secretory granules. The mechanism(s) by which immune tolerance to islet-cell antigens is lost during the development of T1D, remains unclear. Antigenic peptide creation for immune presentation may potentially link to the secretory biology of β cells in a number of ways, including proteasomal digestion of misfolded products, exocytosis and endocytosis of cell-surface products, or antigen release from dying β cells during normal or pathological turnover. In this context, we evaluate the biochemical nature and immunogenicity of the major autoantigens in T1D including (pro)insulin, GAD65, ZnT8, IA2, and ICA69.
    Cold Spring Harbor Perspectives in Medicine 08/2012; 2(8). · 7.56 Impact Factor
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    ABSTRACT: Context: Insulin resistance can be compensated by increased functional pancreatic β-cell mass; otherwise, diabetes ensues. Such compensation depends not only on environmental and genetic factors but also on the baseline β-cell mass from which the expansion originates. Objective: Little is known about assembly of a baseline β-cell mass in humans. Here, we examined formation of β-cell populations relative to other pancreatic islet cell types and associated neurons throughout the normal human lifespan. Design and Methods: Human pancreatic sections derived from normal cadavers aged 24 wk premature to 72 yr were examined by immunofluorescence. Insulin, glucagon, and somatostatin were used as markers for β-, α-, and δ-cells, respectively. Cytokeratin-19 marked ductal cells, Ki67 cell proliferation, and Tuj1 (neuronal class III β-tubulin) marked neurons. Results: Most β-cell neogenesis was observed preterm with a burst of β-cell proliferation peaking within the first 2 yr of life. Thereafter, little indication of β-cell growth was observed. Postnatal proliferation of α- and δ-cells was rarely seen, but a wave of ductal cell proliferation was found mostly associated with exocrine cell expansion. The β-cell to α-cell ratio doubled neonatally, reflecting increased growth of β-cells, but during childhood, there was a 7-fold change in the β-cell to δ-cell ratio, reflecting an additional loss of δ-cells. A close association of neurons to pancreatic islets was noted developmentally and retained throughout adulthood. Negligible neuronal association to exocrine pancreas was observed. Conclusion: Human baseline β-cell population and appropriate association with other islet cell types is established before 5 yr of age.
    The Journal of Clinical Endocrinology and Metabolism 06/2012; 97(9):3197-206. · 6.31 Impact Factor
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    ABSTRACT: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
    Autophagy 04/2012; 8(4):445. · 12.04 Impact Factor
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    Autophagy 04/2012; 8(4):1-100. · 12.04 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
    Autophagy 04/2012; 8(4):445-544. · 12.04 Impact Factor
  • Cristina Alarcon, C Bruce Verchere, Christopher J Rhodes
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    ABSTRACT: Dysfunctional islet amyloid polypeptide (IAPP) biosynthesis and/or processing are thought contribute to formation of islet amyloid in type 2 diabetes. However, it is unclear how normal pro-IAPP biosynthesis and processing are regulated to be able to define such dysfunction. Here, it was found that acute exposure to high glucose concentrations coordinately regulated the biosynthesis of pro-IAPP, proinsulin, and its proprotein convertase PC1/3 in normal isolated rat islets, without affecting their respective mRNA levels. Pro-7B2 biosynthesis, like that of pro-PC2, did not appreciably change, but this was likely due to a much higher expression in pancreatic α-cells masking glucose regulation of their biosynthesis in β-cells. Biosynthesis of pro-SAAS, the putative PC1/3 chaperone, was unaffected by glucose, consistent with its scarce expression in β-cells. We conclude that translational control of pro-IAPP biosynthesis, in parallel to the pro-PC1/3, pro-PC2, and pro-7B2 proprotein-processing endopeptidases/chaperones, is the predominate mechanism to produce IAPP in islet β-cells.
    Endocrinology 03/2012; 153(5):2082-7. · 4.72 Impact Factor
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    ABSTRACT: Insulin receptor substrate-2 (IRS-2) plays an essential role in pancreatic islet β-cells by promoting growth and survival. IRS-2 turnover is rapid in primary β-cells, but its expression is highly regulated at the transcriptional level, especially by glucose. The aim was to investigate the molecular mechanism on how glucose regulates IRS-2 gene expression in β-cells. Rat islets were exposed to inhibitors or subjected to adenoviral vector-mediated gene manipulations and then to glucose-induced IRS-2 expression analyzed by real-time PCR and immunoblotting. Transcription factor nuclear factor of activated T cells (NFAT) interaction with IRS-2 promoter was analyzed by chromatin immunoprecipitation assay and glucose-induced NFAT translocation by immunohistochemistry. Glucose-induced IRS-2 expression occurred in pancreatic islet β-cells in vivo but not in liver. Modulating rat islet β-cell Ca(2+) influx with nifedipine or depolarization demonstrated that glucose-induced IRS-2 gene expression was dependent on a rise in intracellular calcium concentration derived from extracellular sources. Calcineurin inhibitors (FK506, cyclosporin A, and a peptide calcineurin inhibitor [CAIN]) abolished glucose-induced IRS-2 mRNA and protein levels, whereas expression of a constitutively active calcineurin increased them. Specific inhibition of NFAT with the peptide inhibitor VIVIT prevented a glucose-induced IRS-2 transcription. NFATc1 translocation to the nucleus in response to glucose and association of NFATc1 to conserved NFAT binding sites in the IRS-2 promoter were demonstrated. The mechanism behind glucose-induced transcriptional control of IRS-2 gene expression specific to the islet β-cell is mediated by the Ca(2+)/calcineurin/NFAT pathway. This insight into the IRS-2 regulation could provide novel therapeutic means in type 2 diabetes to maintain an adequate functional mass.
    Diabetes 09/2011; 60(11):2892-902. · 7.90 Impact Factor
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    ABSTRACT: Appropriate regulation of insulin receptor substrate 2 (IRS-2) expression in pancreatic β-cells is essential to adequately compensate for insulin resistance. In liver, basal IRS-2 expression is controlled via a temporal negative feedback of sterol regulatory element-binding protein 1 (SREBP-1) to antagonize transcription factors forkhead box class O (FoxO)1/FoxO3a at an insulin response element (IRE) on the IRS-2 promoter. The purpose of the study was to examine if a similar mechanism controlled IRS-2 expression in β-cells. IRS-2 mRNA and protein expression, as well as IRS-2 gene promoter activity, were examined in isolated rat islets. Specific transcription factor association with the IRE on the IRS-2 promoter was examined by chromatin immunoprecipitation (ChIP) assay, and their nuclear translocation was examined by immunofluorescence. A direct in vivo effect of insulin on control of IRS-2 expression in liver and pancreatic islets was also investigated. In IRS-2 promoter-reporter assays conducted in isolated islets, removal of the IRE decreased basal IRS-2 promoter activity in β-cells up to 80%. Activation of IRS signaling in isolated rat islets by insulin/IGF-I (used as an experimental in vitro tool) or downstream constitutive activation of protein kinase B (PKB) significantly decreased IRS-2 expression. In contrast, inhibition of phosphatidylinositol 3-kinase (PI3K) or PKB significantly increased IRS-2 levels in β-cells. ChIP assays indicated that transcription factors FoxO1 and FoxO3a associated with the IRE on the IRS-2 promoter in β-cells in a PI3K/PKB-dependent manner, whereas others, such as SREBP-1, the transcription factor binding to immunoglobulin heavy chain enhancer 3', and the aryl hydrocarbon receptor nuclear translocator (ARNT), did not. However, only FoxO3a, not FoxO1, was capable of driving IRS-2 promoter activity via the IRE in β-cells. In vivo studies showed insulin was able to suppress IRS-2 expression via activation of SREBP-1 in the liver, but this mechanism was not apparent in pancreatic islets from the same animal. The molecular mechanism for feedback control of IRS signaling to decrease IRS-2 expression in liver and β-cells is quite distinct, with a predominant role played by FoxO3a in β-cells.
    Diabetes 09/2011; 60(11):2883-91. · 7.90 Impact Factor
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    ABSTRACT: To determine the subunit expression and functional activation of phagocyte-like NADPH oxidase (Nox), reactive oxygen species (ROS) generation and caspase-3 activation in the Zucker diabetic fatty (ZDF) rat and diabetic human islets. Expression of core components of Nox was quantitated by Western blotting and densitometry. ROS levels were quantitated by the 2',7'-dichlorofluorescein diacetate method. Rac1 activation was quantitated using the gold-labeled immunosorbent assay kit. Levels of phosphorylated p47(phox), active Rac1, Nox activity, ROS generation, Jun NH(2)-terminal kinase (JNK) 1/2 phosphorylation, and caspase-3 activity were significantly higher in the ZDF islets than the lean control rat islets. Chronic exposure of INS 832/13 cells to glucolipotoxic conditions resulted in increased JNK1/2 phosphorylation and caspase-3 activity; such effects were largely reversed by SP600125, a selective inhibitor of JNK. Incubation of normal human islets with high glucose also increased the activation of Rac1 and Nox. Lastly, in a manner akin to the ZDF diabetic rat islets, Rac1 expression, JNK1/2, and caspase-3 activation were also significantly increased in diabetic human islets. We provide the first in vitro and in vivo evidence in support of an accelerated Rac1-Nox-ROS-JNK1/2 signaling pathway in the islet β-cell leading to the onset of mitochondrial dysregulation in diabetes.
    Diabetes 09/2011; 60(11):2843-52. · 7.90 Impact Factor
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    ABSTRACT: Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRb(Nts) neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRb(Nts) neurons with local orexin (OX) neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRb(Nts) neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance.
    Cell metabolism 09/2011; 14(3):313-23. · 17.35 Impact Factor
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    Diabetes 05/2011; 60(5):1370-9. · 7.90 Impact Factor
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    ABSTRACT: Glucose-stimulated insulin secretion [GSIS] involves interplay between small G-proteins and their regulatory factors. Herein, we tested the hypothesis that Arf nucleotide binding site opener [ARNO], a guanine nucleotide-exchange factor [GEF] for the small G-protein Arf6, mediates the functional activation of Arf6, and that ARNO/Arf6 signaling axis, in turn, controls the activation of Cdc42 and Rac1, which have been implicated in GSIS. Molecular biological [i.e., expression of inactive mutants or siRNA] and pharmacological approaches were employed to assess the roles for ARNO/Arf6 signaling pathway in insulin secretion in normal rat islets and INS 832/13 cells. Degrees of activation of Arf6 and Cdc42/Rac1 were quantitated by GST-GGA3 and PAK-1 kinase pull-down assays, respectively. ARNO is expressed in INS 832/13 cells, rat islets and human islets. Expression of inactive mutants of Arf6 [Arf6-T27N] or ARNO [ARNO-E156K] or siRNA-ARNO markedly reduced GSIS in isolated β-cells. SecinH3, a selective inhibitor of ARNO/Arf6 signaling axis, also inhibited GSIS in INS 832/13 cells and rat islets. Stimulatory concentrations of glucose promoted Arf6 activation, which was inhibited by secinH3 or siRNA-ARNO, suggesting that ARNO/Arf6 signaling cascade is necessary for GSIS. SecinH3 or siRNA-ARNO also inhibited glucose-induced activation of Cdc42 and Rac1 suggesting that ARNO/Arf6 might be upstream to Cdc42 and Rac1 activation steps, which are necessary for GSIS. Lastly, co-immunoprecipitation and confocal microscopic studies suggested increased association between Arf6 and ARNO in glucose-stimulated β-cells. These findings provide the first evidence to implicate ARNO in the sequential activation of Arf6, Cdc42 and Rac1 culminating in GSIS.
    Biochemical pharmacology 01/2011; 81(8):1016-27. · 4.25 Impact Factor
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    ABSTRACT: Prolonged exposure of pancreatic beta cells to excessive levels of glucose and fatty acids, referred to as glucolipotoxicity, is postulated to contribute to impaired glucose homeostasis in patients with type 2 diabetes. However, the relative contribution of defective beta cell function vs diminished beta cell mass under glucolipotoxic conditions in vivo remains a subject of debate. We therefore sought to determine whether glucolipotoxicity in rats is due to impaired beta cell function and/or reduced beta cell mass, and whether older animals are more susceptible to glucolipotoxic condition. Wistar rats (2 and 6 months old) received a 72 h infusion of glucose + intravenous fat emulsion or saline control. In vivo insulin secretion and sensitivity were assessed by hyperglycaemic clamps. Ex vivo insulin secretion, insulin biosynthesis and gene expression were measured in isolated islets. Beta cell mass and proliferation were examined by immunohistochemistry. A 72 h infusion of glucose + intravenous fat emulsion in 2-month-old Wistar rats did not affect insulin sensitivity, insulin secretion or beta cell mass. In 6-month-old rats by contrast it led to insulin resistance and reduced insulin secretion in vivo, despite an increase in beta cell mass and proliferation. This was associated with: (1) diminished glucose-stimulated second-phase insulin secretion and proinsulin biosynthesis; (2) lower insulin content; and (3) reduced expression of beta cell genes in isolated islets. In this in vivo model, glucolipotoxicity is characterised by an age-dependent impairment of glucose-regulated beta cell function despite a marked increase in beta cell mass.
    Diabetologia 11/2010; 53(11):2369-79. · 6.49 Impact Factor

Publication Stats

6k Citations
817.58 Total Impact Points

Institutions

  • 2007–2013
    • University of Chicago
      • Department of Medicine
      Chicago, IL, United States
    • Duke University Medical Center
      • Department of Medicine
      Durham, NC, United States
    • University of Queensland 
      • Institute for Molecular Bioscience
      Brisbane, Queensland, Australia
  • 2012
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2009–2012
    • University of Michigan
      • • Life Sciences Institute
      • • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 2011
    • Wayne State University
      • Department of Pharmaceutical Sciences
      Detroit, MI, United States
    • University of Florida
      • Department of Pediatrics
      Gainesville, FL, United States
  • 2002–2007
    • University of Washington Seattle
      • • Department of Medicine
      • • Department of Pharmacology
      Seattle, Washington, United States
  • 2000–2006
    • Pacific Northwest Diabetes Research Institute
      Seattle, Washington, United States
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 1999–2000
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1998–2000
    • University of Texas Southwestern Medical Center
      • Department of Internal Medicine
      Dallas, TX, United States
  • 1992–2000
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Biochemistry and Molecular Biology
      New Orleans, LA, United States