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Morris J Birnbaum

Publications and source records attributed to Morris J Birnbaum.

At least 37 records · Page 2Linked to original sources
PubMed2004

AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus.

Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.

Adenylate Kinase↗
PubMed2004

Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.

AKT-GSK3beta signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3beta at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3beta signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.

Antipsychotic Agents↗
PubMed2004

On the InterAktion between hexokinase and the mitochondrion.

The protein kinase Akt is now well recognized as a potent inhibitor of apoptosis. Work published by Majewski et al. in the December 3rd issue of Molecular Cell indicates that a major pathway by which Akt suppresses cell death is by stimulating the translocation of hexokinase to the mitochondrion. Hexokinase, in turn, antagonizes the release of mitochondrial cytochrome C.

Animals↗
PubMed2004

Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: role in absorption and differentiation.

BACKGROUND AND AIMS: In intestinal Na absorptive cells, phosphatidylinositol 3-kinase (PI 3-K) is involved in rapid epidermal growth factor (EGF) stimulation of Na absorption by the brush border membrane (BBM) Na(+)/H(+) exchanger NHE3. However, how NHE3 is regulated by the PI 3-K pathway and the role of Akt2 are poorly defined. METHODS: The localization of Akt, PI 3-K, and NHE3 was determined by either immunocytochemistry and/or membrane fractionation using OptiPrep density gradient centrifugation. RESULTS: In ileum, active total Akt was present most in the villi and basal layer of the crypts, and Akt2 was mostly in villi. In villus cells, PI 3-K and Akt2 were mostly at the apical surface at which they were present partially in lipid rafts (LR). EGF increased PI 3-K and active Akt2 in ileal BBM at the same time that it increased PI 3-K-dependent trafficking of NHE3 to BBM and stimulation of Na absorption. However, Akt2 was only active in the detergent soluble (DS) pool and not LR of ileal BBM, which correlated with the presence of PTEN in LR. In Caco-2 cells, while EGF stimulated BB NHE3, Akt2 was active in both LR and DS pools. This correlated with the lack of PTEN in the LR of Caco-2 membranes. Akt2 also correlated with epithelial cell differentiation. Akt2 amount and activity were greater in differentiated than undifferentiated Caco-2 cells. CONCLUSIONS: These results suggest that LR may play an important role in determining the function of PI 3-K/Akt2 signaling, including stimulation of intestinal Na absorption. These results also suggest that LR-associated Akt2 may be involved in enterocyte differentiation.

Animals↗
PubMed2004

AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury.

AMP-activated protein kinase (AMPK) is an important regulator of diverse cellular pathways in the setting of energetic stress. Whether AMPK plays a critical role in the metabolic and functional responses to myocardial ischemia and reperfusion remains uncertain. We examined the cardiac consequences of long-term inhibition of AMPK activity in transgenic mice expressing a kinase dead (KD) form of the enzyme. The KD mice had normal fractional shortening and no heart failure, cardiac hypertrophy, or fibrosis, although the in vivo left ventricular (LV) dP/dt was lower than that in WT hearts. During low-flow ischemia and postischemic reperfusion in vitro, KD hearts failed to augment glucose uptake and glycolysis, although glucose transporter content and insulin-stimulated glucose uptake were normal. KD hearts also failed to increase fatty acid oxidation during reperfusion. Furthermore, KD hearts demonstrated significantly impaired recovery of LV contractile function during postischemic reperfusion that was associated with a lower ATP content and increased injury compared with WT hearts. Caspase-3 activity and TUNEL-staining were increased in KD hearts after ischemia and reperfusion. Thus, AMPK is responsible for activation of glucose uptake and glycolysis during low-flow ischemia and plays an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.

AMP-Activated Protein Kinases↗
PubMed2003

ADP-ribosylation factor 6 regulates insulin secretion through plasma membrane phosphatidylinositol 4,5-bisphosphate.

ADP-ribosylation factor 6 (ARF6) is a small GTP-binding protein that regulates peripheral vesicular trafficking and actin cytoskeletal dynamics, and it has been implicated as critical to regulated secretion. Expression of a dominant-inhibitory ARF6 mutant, ARF6(T27N), impaired glucose-, depolarization-, and gamma-thio-GTP-stimulated insulin secretion in the pancreatic beta cell line, MIN6. In response to depolarization, MIN6 cells expressing ARF6(T27N) displayed an unaltered initial fast phase but an impaired subsequent slow phase of insulin secretion. Actin cytoskeletal disassembly with latrunculin A enhanced insulin secretion, whereas stabilization with jasplakinolide inhibited secretion, consistent with the actin cytoskeleton serving as a barrier to exocytosis in these cells. ARF6(T27N) led to a depolarization-dependent reduction in the levels of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] with a time course that paralleled the inhibition of secretion. Moreover, blockade of PI(4,5)P2-dependent events by expression of a lipid-binding protein resulted in inhibition of depolarization-induced secretion in a manner identical to ARF6(T27N). These results indicate that ARF6 is required to sustain adequate levels of PI(4,5)P2 during periods of increased PI(4,5)P2 metabolism such as regulated secretion.

ADP-Ribosylation Factor 6↗
PubMed2003

Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B.

Recent data have implicated the serine/threonine protein kinase Akt/protein kinase B (PKB) in a diverse array of physiological pathways, raising the question of how biological specificity is maintained. Partial clarification derived from the observation that mice deficient in either of the two isoforms, Akt1/PKBalpha or Akt2/PKBbeta, demonstrate distinct abnormalities, i.e. reduced organismal size or insulin resistance, respectively. However, the question still persists as to whether these divergent phenotypes are due exclusively to tissue-specific differences in isoform expression or distinct capacities for signaling intrinsic to the two proteins. Here we show that Akt2/PKBbeta-/- adipocytes derived from immortalized mouse embryo fibroblasts display significantly reduced insulin-stimulated hexose uptake, clearly establishing that the partial defect in glucose disposal in these mice derives from lack of a cell autonomous function of Akt2/PKBbeta. Moreover, in adipocytes differentiated from primary fibroblasts or immortalized mouse embryo fibroblasts, and brown preadipocytes the absence of Akt2/PKBbeta resulted in reduction of insulin-induced hexose uptake and glucose transporter 4 (GLUT4) translocation, whereas Akt1/PKBalpha was dispensable for this effect. Most importantly, hexose uptake and GLUT4 translocation were completely restored after re-expression of Akt2/PKBbeta in Akt2/PKBbeta-/- adipocytes, but overexpression of Akt1/PKBalpha at comparable levels was ineffective at rescuing insulin action to normal. These results show that the Akt1/PKBalpha and Akt2/PKBbeta isoforms are uniquely adapted to preferentially transmit distinct biological signals, and this property is likely to contribute significantly to the ability of Akt/PKB to play a role in diverse processes.

Adipose Tissue, Brown↗
PubMed2003

Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis In 3T3-L1 adipocytes.

AMP-activated protein kinase (AMPK) is a phylogenetically conserved intracellular energy sensor that has been implicated as a major regulator of glucose and lipid metabolism in mammals. However, its possible role in mediating or influencing the adrenergic control of lipolysis in adipocytes remains uncertain. In this study, we utilized the murine cultured preadipocyte line 3T3-L1 to examine this question. Treatment of adipocytes with isoproterenol or forskolin promoted the phosphorylation of AMPK at a critical activating Thr-172 residue in a dose- and time-dependent manner. This correlated well with a stimulation of the activity of AMPK, as measured in the immune complex. Analogs of cAMP mimicked the effect of isoproterenol and forskolin on AMPK phosphorylation. Treatment of adipocytes with insulin reduced both basal and forskolin-induced AMPK phosphorylation via a pathway dependent on phosphatidylinositol 3'-kinase. Overexpression of a dominant-inhibitory mutant of AMPK blocked isoproterenol-induced lipolysis by approximately 50%. These data indicate that there exists a novel pathway by which cAMP can lead to the activation of AMPK, and in adipocytes, this is required for maximal activation of lipolysis.

3T3-L1 Cells↗
PubMed2003

Lipolysis: more than just a lipase.

Successful adaptation to starvation in mammals depends heavily on the regulated mobilization of fatty acids from triacylglycerols stored in adipose tissue. Although it has long been recognized that cyclic AMP represents the critical second messenger and hormone-sensitive lipase (HSL)**Abbreviations used in this paper: ADRP, adipocyte differentiation-related protein; HSL, hormone-sensitive lipase; PKA, protein kinase A; TAG, triacylglycerol. the rate-determining enzyme for lipolysis, simple activation of the enzyme has failed to account for the robust augmentation of fatty release in response to physiological agonists. In this issue, Sztalryd et al. (2003) provide convincing support to the notion that the subcellular compartmentalization of lipase also regulates lipolysis, and, more importantly, that proteins other than HSL are localized to the lipid droplet and are indispensable for its optimal hydrolysis.

Adipose Tissue↗
PubMed2003

Identification of a proline-rich Akt substrate as a 14-3-3 binding partner.

Akt (also called protein kinase B) is one of the major downstream targets of the phosphatidylinositol 3-kinase pathway. This protein kinase has been implicated in insulin signaling, stimulation of cellular growth, and inhibition of apoptosis as well as transformation of cells. Although a number of cellular proteins have been identified as putative targets of the enzyme, additional substrates may play a role in the varied responses elicited by this enzyme. We have used a combination of 14-3-3 binding and recognition by an antibody to the phosphorylation consensus of the enzyme to identify and isolate one of the major substrates of Akt, which is also a 14-3-3 binding protein. This 40-kDa protein, designated PRAS40, is a proline-rich Akt substrate. Demonstration that it is a substrate of Akt was accomplished by showing that 1) PRAS40 was phosphorylated in vitro by purified Akt on the same site that was phosphorylated in insulin-treated cells; 2) activation of an inducible Akt was alone sufficient to stimulate the phosphorylation of PRAS40; and 3) cells lacking Akt1 and Akt2 exhibit a diminished ability to phosphorylate this protein. Thus, PRAS40 is a novel substrate of Akt, the phosphorylation of which leads to the binding of this protein to 14-3-3.

14-3-3 Proteins↗
PubMed2003

The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity.

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKalpha2 catalytic subunit gene was inactivated. AMPKalpha2(-/-) mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKalpha2(-/-) pancreatic islets, glucose- and L-arginine-stimulated insulin secretion were not affected. AMPKalpha2(-/-) mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKalpha2(-/-) muscles. These data indicate that AMPKalpha2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKalpha2(-/-) mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKalpha2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity.

AMP-Activated Protein Kinases↗
PubMed2003

GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor-stimulated muscle glucose utilization.

Recent evidence suggests the existence of a hepatoportal vein glucose sensor, whose activation leads to enhanced glucose use in skeletal muscle, heart, and brown adipose tissue. The mechanism leading to this increase in whole body glucose clearance is not known, but previous data suggest that it is insulin independent. Here, we sought to further determine the portal sensor signaling pathway by selectively evaluating its dependence on muscle GLUT4, insulin receptor, and the evolutionarily conserved sensor of metabolic stress, AMP-activated protein kinase (AMPK). We demonstrate that the increase in muscle glucose use was suppressed in mice lacking the expression of GLUT4 in the organ muscle. In contrast, glucose use was stimulated normally in mice with muscle-specific inactivation of the insulin receptor gene, confirming independence from insulin-signaling pathways. Most importantly, the muscle glucose use in response to activation of the hepatoportal vein glucose sensor was completely dependent on the activity of AMPK, because enhanced hexose disposal was prevented by expression of a dominant negative AMPK in muscle. These data demonstrate that the portal sensor induces glucose use and development of hypoglycemia independently of insulin action, but by a mechanism that requires activation of the AMPK and the presence of GLUT4.

Adenylate Kinase↗
PubMed2003

Platelet-derived growth factor (PDGF) stimulates glucose transport in 3T3-L1 adipocytes overexpressing PDGF receptor by a pathway independent of insulin receptor substrates.

Insulin is unique among growth factors and hormones in its ability to control metabolic functions such as the stimulation of glucose uptake and glucose transporter (GLUT4) translocation in physiological target tissues, such as muscle and adipose cells. Nonetheless, the mechanisms underlying this specificity have remained incompletely understood, particularly in view of the ability of some growth factors to mimic insulin-dependent early signaling events. In this study, we have probed the basis of insulin specificity by overexpressing in hormone-responsive 3T3-L1 adipocytes wild-type platelet-derived growth factor (PDGF) receptor (PDGFR)-beta and selected, informative mutant receptor proteins. We show that such adipocytes overexpressing wild-type PDGFR on exposure to cognate growth factor activate glucose transport, GLUT4 translocation, and the serine-threonine protein kinase Akt/protein kinase B to a degree comparable with that produced in response to insulin. In addition, PDGF elicits the robust generation of phosphatidylinositol-3,4,5-trisphosphate in vivo in PDGFR-overexpressing 3T3-L1 adipocytes. Expression of PDGFR-beta mutant proteins demonstrates that these responses require the presence of an intact phosphatidylinositol 3-kinase (PI3K)-binding site on the overexpressed PDGF receptor. Furthermore, PDGF stimulates these effects independent of insulin receptor substrate(IRS)-1 or IRS-2 tyrosine phosphorylation or docking to activated PI3K. These data demonstrate that 1) the basis of insulin-specific glucose transport in cultured adipocytes is the low level of receptors for other growth factors and 2) in the presence of adequate receptors, PDGF is fully capable of activating glucose transport in a manner requiring PI3K and subsequent phosphatidylinositol-3,4,5-trisphosphate accumulation but independent of insulin, insulin receptor, and IRS proteins.

3T3 Cells↗
PubMed2002

AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation.

Mitochondrial biogenesis is a critical adaptation to chronic energy deprivation, yet the signaling mechanisms responsible for this response are poorly understood. To examine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved fuel sensor, in mitochondrial biogenesis we studied transgenic mice expressing a dominant-negative mutant of AMPK in muscle (DN-AMPK). Both DN-AMPK and WT mice were treated with beta-guanidinopropionic acid (GPA), a creatine analog, which led to similar reductions in the intramuscular ATPAMP ratio and phosphocreatine concentrations. In WT mice, GPA treatment resulted in activation of muscle AMPK and mitochondrial biogenesis. However, the same GPA treatment in DN-AMPK mice had no effect on AMPK activity or mitochondrial content. Furthermore, AMPK inactivation abrogated GPA-induced increases in the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and calciumcalmodulin-dependent protein kinase IV (both master regulators of mitochondrial biogenesis). These data demonstrate that by sensing the energy status of the muscle cell, AMPK is a critical regulator involved in initiating mitochondrial biogenesis.

Adenine Nucleotides↗
PubMed2002

Akt1 regulates a JNK scaffold during excitotoxic apoptosis.

Cell survival is determined by a balance among signaling cascades, including those that recruit the Akt and JNK pathways. Here we describe a novel interaction between Akt1 and JNK interacting protein 1 (JIP1), a JNK pathway scaffold. Direct association between Akt1 and JIP1 was observed in primary neurons. Neuronal exposure to an excitotoxic stimulus decreased the Akt1-JIP1 interaction and concomitantly increased association between JIP1 and JNK. Akt1 interaction with JIP1 inhibited JIP1-mediated potentiation of JNK activity by decreasing JIP1 binding to specific JNK pathway kinases. Consistent with this view, neurons from Akt1-deficient mice exhibited higher susceptibility to kainate than wild-type littermates. Overexpression of Akt1 mutants that bind JIP1 reduced excitotoxic apoptosis. These results suggest that Akt1 binding to JIP1 acts as a regulatory gate preventing JNK activation, which is released under conditions of excitotoxic injury.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Role of Akt/protein kinase B in metabolism.

Since its discovery more than a decade ago, the Ser/Thr kinase Akt/PKB (protein kinase B) has been recognized as being remarkably well conserved across a broad range of species and involved in a diverse array of cellular processes. Among its many roles, Akt appears to be common to signaling pathways that mediate the metabolic effects of insulin in several physiologically important target tissues. Refining our understanding of those pivotal molecular components that normally coordinate insulin action throughout the body is essential for a full understanding of insulin resistance in diabetes mellitus and ultimately the successful treatment of this disease.

Adipose Tissue↗
PubMed2002

RhoGAP: the next big thing for small mice?

The size of an organism is determined by the number and size of its constituent cells. The insulin/IGF-1 signaling systems have been long recognized to play a critical role in the determination of body size. Now the generation of mice deficient for a RhoGAP suggests that this small G protein might also regulate the growth of animals.

Animals↗