Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Norepinephrine-induced thermogenesis was substantial in adipocytes from brown adipose tissue (BAT) of cold-acclimated guinea pigs but absent in adipocytes from BAT of warm-acclimated guinea pigs. There was no thermogenic response to any beta 3-adrenergic agonist (CL-316,243, ZD-7114, BRL-28410, CGP-12177). The receptor was characterized as a beta 1-adrenoceptor. Adrenergic agonists stimulated adenylate cyclase in membranes from BAT of both warm- and cold-acclimated guinea pigs also via a beta 1-adrenoceptor; beta 3-adrenergic agonists had no effect. Glucose transport by brown adipocytes from warm-acclimated guinea pigs was not stimulated by either norepinephrine or insulin. Cold acclimation induced the appearance of stimulation of glucose transport by norepinephrine in association with the appearance of a large capacity for thermogenesis, but there was little improvement in response to insulin. GLUT4 was present in membranes from BAT of both warm- and cold-acclimated guinea pigs. Insulin is known to have an antilipolytic effect on both BAT and white adipose tissue of guinea pigs. Thus there is a selective lack of insulin-regulated glucose transport that is not improved by cold acclimation. Guinea pigs may have a mutated component of the translocation mechanism for GLUT4. beta 3-Adrenoceptors appear to be absent in brown adipocytes of adult guinea pigs, as in white adipocytes of guinea pigs, yet are known to be present in the gut. Tissue-specific expression of beta 3-adrenergic receptors in guinea pigs may differ from that in rats, in which receptors are expressed in the adipose tissues and gut.
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PMID:Apparent lack of beta 3-adrenoceptors and of insulin regulation of glucose transport in brown adipose tissue of guinea pigs. 784 Mar 45

We have previously described the ability of arachidonic acid (AA) to regulate GLUT4 gene expression (Tebbey, P.W., McGowan, K.M., Stephens, J.M., Buttke, T.M., and Pekala, P.H. (1994) J. Biol. Chem. 269, 639-644). Chronic exposure (48 h) of fully differentiated 3T3-L1 cells to AA resulted in an approximately 90% suppression of GLUT4 mRNA accumulation. This decrease was demonstrated to be due to a 50% decrease in GLUT4 gene transcription as well as a destabilization of the GLUT4 message (t1/2 decreased from 8.0 to 4.6 h). In the current study we have identified, at least in part, the mechanism by which AA exerts its effects on GLUT4 expression. Compatible with a cyclooxygenase mediated event, the AA-induced suppression of GLUT4 mRNA was abolished by pretreating the cells with the inhibitor, indomethacin. Consistent with this observation, exposure of the cells to 10 microM PGE2 mimicked the effect of AA, in contrast to products of the lipoxygenase pathway which were unable to suppress GLUT4 mRNA content. Quantification of the conversion of AA to PGE2 demonstrated a 50-fold increase in PGE2 released into the media within 7 h of AA addition. Cyclic AMP levels were also increased 50-fold with AA treatment consistent with PGE2 activation of adenylate cyclase. Various long chain fatty acids, including the nonmetabolizable analog of AA, eicosatetraenoic acid (ETYA), also decreased GLUT4 mRNA levels. The effect of ETYA, a potent inhibitor of both lipo- and cyclooxygenases and a potent activator of peroxisome proliferator activated receptors (PPARs), suggested the presence of a second pathway where non-metabolized fatty acid functioned to suppress GLUT4 mRNA levels. Further support for a PPAR-mediated mechanism was obtained by exposure of the cells to the classic PPAR activator, clofibrate, which resulted in a approximately 75% decrease in GLUT4 mRNA content. Nuclear extracts prepared from the adipocytes contained a protein complex that bound to the PPAR responsive element (PPRE) found in the promoter of the fatty acyl-CoA oxidase gene. When the adipocytes were treated with either AA or ETYA, binding to the PPRE was disrupted, consistent with an ability of these fatty acids to control gene expression by altering the occupation of a PPRE. However, a perfect PPRE has yet to be identified in the GLUT4 promoter, but this does not rule the possibility of a PPAR playing an indirect role in the AA-induced GLUT4 mRNA suppression.
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PMID:Regulation of GLUT4 gene expression by arachidonic acid. Evidence for multiple pathways, one of which requires oxidation to prostaglandin E2. 855 42

Deficiency of the G protein subunit G alpha i2 that is known to mediate the inhibitory control of adenylylcyclase impairs insulin action [11]. Using the promoter for the phosphoenolpyruvate carboxykinase gene, conditional tissue-specific expression of the constitutively active mutant form (Q205L) of G alpha i2 was achieved in mice harboring the transgene. Expression of Q205L G alpha i2 was detected in liver and adipose tissue of transgenic mice. Whereas the G alpha i2 deficient mice displayed blunted glucose tolerance, the Q205L G alpha i2 expressing mice displayed enhanced glucose tolerance. Hexose transport and the recruitment of GLUT4, but not GLUT1, transporters to the membrane were elevated in adipocytes from Q205L G alpha i2 expressing mice in the absence of insulin. Additionally, hepatic glycogen synthase was found to be activated in Q205L G alpha i2 expressing mice, in the absence of the administration of insulin. Serum insulin levels in transgenic mice fasted overnight were equivalent to those of their control littermates. These data demonstrate that much as G alpha i2 deficiency leads to insulin resistance, expression of Q205L constitutively active G alpha i2 mimics insulin action in vivo, reflecting a permissive role of G alpha i2 in signaling via this growth factor receptor tyrosine kinase linked pathway.
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PMID:Conditional, tissue-specific expression of Q205L G alpha i2 in vivo mimics insulin action. 915 Dec 6

The present study investigated whether alterations in the muscle high energy phosphate state initiates the contraction-induced increase in skeletal muscle GLUT4 protein concentration. Sprague-Dawley rats were provided either a normal or a 2% beta-guanidinoproprionic acid (beta-GPA) diet for 8 weeks and then the gastrocnemius of one hind limb was subjected to 0, 14 or 28 days of chronic (24 h day-1) low-frequency electrical stimulation (10 Hz). The beta-GPA diet, in the absence of electrical stimulation, significantly reduced ATP, creatine phosphate, creatine and inorganic phosphate and elevated GLUT4 protein concentration by 60% without altering adenylate cyclase activity or cAMP concentration. Following 14 days of electrical stimulation, GLUT4 protein concentration was elevated above non-stimulated muscle in both groups but was significantly more elevated in the beta-GPA group. Concurrent with this greater rise in GLUT4 protein concentration was a greater decline in the high energy phosphates and a greater rise in cAMP. After 28 days of electrical stimulation, GLUT4 protein concentration and cAMP stabilized and was not different between diet treatments. However, the high energy phosphates were significantly higher in the normal diet rats as opposed to the beta-GPA rats. These findings therefore suggest that a reduction in cellular energy supply initiates the contraction-induced increase in muscle GLUT4 protein concentration, but that a rise in cAMP may potentiate this effect.
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PMID:Effect of chronic electrical stimulation and beta-GPA diet on GLUT4 protein concentration in rat skeletal muscle. 971 37

Endothelin-1 (ET-1) is a 21-amino-acid peptide that binds to G-protein-coupled receptors to evoke biological responses. Previously we have shown that ET-1 stimulates glucose uptake in 3T3-L1 adipocytes and neonatal rat cardiomyocytes, but the mechanism is not completely understood. ET-1 is known to modulate intracellular Ca(2+) and cAMP levels. Depletion of intracellular Ca(2+) by treating 3T3-L1 adipocytes with EDTA and 1,2-bis(2-amino-5-methylphenoxy)ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxymethyl ester (MAPTAM) did not have a significant effect on ET-1-induced glucose uptake. Forskolin, a potent stimulator which stimulates adenylate cyclase and increases the intracellular cAMP level, partially inhibited insulin-stimulated glucose uptake in 3T3-L1 cells, but had no significant impact on the effect of ET-1. Forskolin also did not show an effect on the tyrosine phosphorylation of a 75 kDa protein induced by ET-1. Glucosamine treatment causes insulin resistance in cells, possibly by entering the hexosamine biosynthetic pathway. In neonatal rat cardiomyocytes, glucosamine treatment blocked both insulin and ET-1-stimulated glucose uptake and also eliminated the translocation of IRAP, an aminopeptidase in GLUT4-containing vesicles, from the cytoplasm to the plasma membrane. These results suggest that ET-1-induced glucose uptake is independent of its effects on modulating intracellular Ca(2+) and cAMP levels, but is likely linked to the hexosamine biosynthetic pathway.
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PMID:Endothelin-stimulated glucose uptake: effects of intracellular Ca(2+), cAMP and glucosamine. 1219 36

Previous reports suggest that parathyroid hormone (PTH) is associated with insulin resistance. This research investigated the effects of PTH on insulin signaling in differentiated 3T3-L1 adipocytes. PTH (10 nM, 24 h) treatment induced a reduction in insulin-stimulated glucose uptake, AKT activity (phosphorylated AKT/total AKT protein expression) and a decrease in GLUT4 and IRS-1 protein expression compared to vehicle treated controls in differentiated adipocytes. PTH treatment also induced increased phosphorylation of IRS-1 on serine 307, which suppresses insulin signaling. In addition, treatment of cells with adenyl cyclase inhibitor SQ52236 ameliorated the effects of PTH on insulin-stimulated glucose uptake, whereas inhibition of phospholipase C alpha (U73122) did not significantly alter the effects of PTH. Thus, PTH treatment of differentiated 3T3-L1 adipocytes suppresses insulin-stimulated glucose uptake and insulin signaling via cAMP pathway, potentially through the phosphorylation of IRS-1 at serine 307.
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PMID:Parathyroid hormone suppresses insulin signaling in adipocytes. 1952 29