Biomedical subjects

G Zhou

Publications and source records attributed to G Zhou.

At least 37 records · Page 2Linked to original sources

PubMed2001

Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR) alpha. PPAR alpha fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expresson.

We compared the ability of rat and human hepatocytes to respond to fenofibric acid and a novel potent phenylacetic acid peroxisome proliferator-activated receptor (PPAR) alpha agonist (compound 1). Fatty acyl-CoA oxidase (FACO) activity and mRNA were increased after treatment with either fenofibric acid or compound 1 in rat hepatocytes. In addition, apolipoprotein CIII mRNA was decreased by both fenofibric acid and compound 1 in rat hepatocytes. Both agonists decreased apolipoprotein CIII mRNA in human hepatocytes; however, very little change in FACO activity or mRNA was observed. Furthermore, other peroxisome proliferation (PP)-associated genes including peroxisomal 3-oxoacyl-CoA thiolase (THIO), peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), peroxisomal membrane protein-70 (PMP-70) were not regulated by PPAR alpha agonists in human hepatocytes. Moreover, other genes that are regulated by PPAR alpha ligands in human hepatocytes such as mitochondrial HMG-CoA synthase and carnitine palmitoyl transferase-1 (CPT-1) were also regulated in HepG2 cells by PPAR alpha agonists. Several stably transfected HepG2 cell lines were established that overexpressed human PPAR alpha to levels between 6- and 26-fold over normal human hepatocytes. These PPAR alpha-overexpressing cells had higher basal mRNA levels of mitochondrial HMG-CoA synthase and CPT-1; however, basal FACO mRNA levels and other PP-associated genes including THIO, HD, or PMP-70 mRNA were not substantially affected. In addition, FACO, THIO, HD, and PMP-70 mRNA levels did not increase in response to PPAR alpha agonist treatment in the PPAR alpha-overexpressing cells, although mitochondrial HMG-CoA synthase and CPT-1 mRNAs were both induced. These results suggest that other factors besides PPAR alpha levels determine the species-specific response of human and rat hepatocytes to the induction of PP.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2001

[Isolation of high-quality genomic DNA from plants].

In order to isolate high-quality genomic DNA from medicinal plant tissues enriching polyphenols and polysaccharides, a simple and rapid method based on CTAB extraction for isolating high-quality intact DNA was established by modifying several existing methods. With this technique, the absorbance ratio (A260/A280) of DNAs obtained from fresh and/or dried roots of Panax ginseng, P. Quinquefolius and P. notoginseng was 1.8 approximately. The restriction fragments of DNAs were directly digested with restriction enzyme (EcoR I/Mse I), linked up by T4 DNA ligase and amplified by nested PCR. Reproducible amplified fragment length polymorphism (AFLP) genomic DNA fingerprinting profiles were established with the isolated DNAs. The results demonstrate that the modified technique may be efficient and reliable in isolating high-quality and high-molecular-weight DNAs from fresh and/or dried medicinal plants containing a high content of polyphenols and polysaccharides. We expect that this method can also be applied to other plants.

DNA Fingerprinting↗

PubMed2001

Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788.

Current treatment of Alzheimer's Disease (AD) requires acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft. Another mechanism by which ACh levels can be increased is blockade of presynaptic M2 muscarinic autoreceptors that regulate ACh release. An antagonist designed for this purpose must be highly selective for M2 receptors to avoid blocking postsynaptic M1 receptors, which mediate the cognitive effects of ACh. Structure-activity studies of substituted methylpiperadines led to the synthesis of 4-[4-[1(S)-[4-[(1,3-benzodioxol-5-yl)sulfonyl]phenyl]ethyl]-3(R)-methyl-1-piperazinyl]-4-methyl-1-(propylsulfonyl)piperidine. This compound, SCH 72788, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 0.5 nM, and its affinity at M1 receptors is 84-fold lower. SCH 72788 is a functional M2 antagonist that competitively inhibits the ability of the agonist oxotremorine-M to inhibit adenylyl cyclase activity. In an in vivo microdialysis paradigm, SCH 72788 increases ACh release from the striatum of conscious rats. The compound is also active in a rodent model of cognition, the young rat passive avoidance response paradigm. The effects of SCH 72788 suggest that M2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias.

Acetylcholine↗

PubMed2001

Organization of uroplakin subunits: transmembrane topology, pair formation and plaque composition.

The apical surfaces of urothelial cells are almost entirely covered with plaques consisting of crystalline, hexagonal arrays of 16 nm uroplakin particles. Although all four uroplakins, when SDS-denatured, can be digested by chymotrypsin, most uroplakin domains in native urothelial plaques are resistant to the enzyme, suggesting a tightly packed structure. The only exception is the C-terminal, cytoplasmic tail of UPIII (UPIII) which is highly susceptible to proteolysis, suggesting a loose configuration. When uroplakins are solubilized with 2% octylglucoside and fractionated with ion exchangers, UPIa and UPII were bound as a complex by a cation exchanger, whereas UPIb and UPIII were bound by an anion exchanger. This result is consistent with the fact that UPIa and UPIb are cross-linked to UPII and UPIII, respectively, and suggests that the four uroplakins form two pairs consisting of UPIa/II and UPIb/III. Immunogold labelling using a new mouse monoclonal antibody, AU1, revealed that UPIII is present in all urothelial plaques, indicating that the two uroplakin pairs are not segregated into two different types of urothelial plaque and that all plaques must have a similar uroplakin composition. Taken together, these results indicate that uroplakins form a tightly packed structure, that the four uroplakins interact specifically forming two pairs, and that both uroplakin pairs are required for normal urothelial plaque formation.

Amino Acid Sequence↗

PubMed2001

The pattern of gene expression in human CD15+ myeloid progenitor cells.

We performed a genome-wide analysis of gene expression in primary human CD15(+) myeloid progenitor cells. By using the serial analysis of gene expression (SAGE) technique, we obtained quantitative information for the expression of 37,519 unique SAGE-tag sequences. Of these unique tags, (i) 25% were detected at high and intermediate levels, whereas 75% were present as single copies, (ii) 53% of the tags matched known expressed sequences, 34% of which were matched to more than one known expressed sequence, and (iii) 47% of the tags had no matches and represent potentially novel genes. The correct genes were confirmed by application of the generation of longer cDNA fragments from SAGE tags for gene identification (GLGI) technique for high-copy tags with multiple matches. A set of genes known to be important in myeloid differentiation were expressed at various levels and used different spliced forms. This study provides a normal baseline for comparison of gene expression in myeloid diseases. The strategy of using SAGE and GLGI techniques in this study has broad applications to the genome-wide identification of expressed genes.

Biomarkers↗

PubMed2001

Miniaturized pyrosequencer for DNA analysis with capillaries to deliver deoxynucleotides.

As the human genome project proceeds, various types of DNA analysis tools are required for life sciences and medical sciences including DNA diagnostics. For example, a small DNA sequencer for sequencing a short DNA is required for bed-side DNA testing as well as DNA analysis in a small laboratory. Here, a new handy DNA sequencing system (pyrosequencer) based on the detection of inorganic pyrophosphate (PPi) released by polymerase incorporation is demonstrated. The system uses the bioluminescence detection system. The key point for the miniaturized DNA sequencer is to make a deoxynucleotide triphosphate (dNTP) delivery system small and inexpensive. It has been realized by using narrow capillaries to connect a reaction chamber and four dNTP reservoirs. Each dNTP is introduced into the reaction chamber by applying a pressure to the reservoir. Compared with other microdispensers, it is much cheaper and easier. By optimizing the conditions, an excellent sequencing ability is achieved while it is a simple and inexpensive system. In most cases, more than 40 bases can be successfully sequenced. A homopolymeric region, which can not be easily sequenced by a conventional gel-based DNA sequencer, is readily sequenced with this system. The new system is successfully applied to sequence a GC rich region or a region close to a priming region where misreading frequently occurs. A rapid analysis for a short DNA was easily achieved with this small instrument.

Base Sequence↗

PubMed2001

Serotonin modulates locomotory behavior and coordinates egg-laying and movement in Caenorhabditis elegans.

Biogenic amines have been implicated in the modulation of neural circuits involved in diverse behaviors in a wide variety of organisms. In the nematode C. elegans, serotonin has been shown to modulate the temporal pattern of egg-laying behavior. Here we show that serotonergic neurotransmission is also required for modulation of the timing of behavioral events associated with locomotion and for coordinating locomotive behavior with egg-laying. Using an automated tracking system to record locomotory behavior over long time periods, we determined that both the direction and velocity of movement fluctuate in a stochastic pattern in wild-type worms. During periods of active egg-laying, the patterns of reversals and velocity were altered: velocity increased transiently before egg-laying events, while reversals increased in frequency following egg-laying events. The temporal coordination between egg-laying and locomotion was dependent on the serotonergic HSN egg-laying motorneurons as well as the decision-making AVF interneurons, which receive synaptic input from the HSNs. Serotonin-deficient mutants also failed to coordinate egg-laying and locomotion and exhibited an abnormally low overall reversal frequency. Thus, serotonin appears to function specifically to facilitate increased locomotion during periods of active egg-laying, and to function generally to modulate decision-making neurons that promote forward movement.

Algorithms↗

PubMed2001

The pattern of gene expression in mouse Gr-1(+) myeloid progenitor cells.

To understand the pattern of gene expression in mouse myeloid progenitor cells, we carried out a genome-wide analysis of gene expression in mouse bone marrow Gr-1(+) cells using SAGE and GLGI techniques. We identified 22,033 unique SAGE tags with quantitative information from 73,869 collected SAGE tags. Among these unique tags, 64% match known sequences, including many genes important for myeloid differentiation, and 36% have no matches to known sequences and are likely to represent novel genes. We compared the expression of mouse Gr-1(+) and human CD15(+) myeloid progenitor cells and showed that the pattern of gene expression of these two cell populations had some similarities. We also compared the expression of mouse Gr-1(+) myeloid progenitor cells with that of mouse brain tissue and found a highly tissue-specific manner of gene expression in these two samples. Our data provide a basis for studying altered gene expression in myeloid disorders using mouse models.

Animals↗

PubMed2001

Use of homogeneous time-resolved fluorescence energy transfer in the measurement of nuclear receptor activation.

Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that mediate the effects of hormones and other endogenous ligands to regulate the expression of specific genes. NRs are clearly important targets for drug discovery. Ligand-dependent protein-protein interactions between NRs and NR coactivators (NRCoAs) are a critical step in regulation of transcription. Homogeneous time-resolved fluorescence (HTRF) energy transfer technology is sensitive, homogeneous, and nonradioactive. These characteristics make this approach attractive for developing high-throughput screening assays. The long-lived nature of the fluorescence of europium cryptate combined with a time delay in reading facilitates the homogeneous nature of the assay. Importantly, the introduction of lanthanides (with R0 values as great as 90 A in HTRF) make HTRF amenable to be used for protein-protein interactions. In this article we review, using peroxisome proliferator-activated receptor (PPAR)gamma as a model system, a novel approach for characterizing the ligand-dependent interaction between NR and NRCoA using HTRF technology and its potential uses in small-molecule screening, profiling selectivity of NR-NRCoA paired interactions, and profiling NR ligands as agonists versus partial agonists or antagonists.

CREB-Binding Protein↗

PubMed2001

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

Alzheimer Disease↗

PubMed2001

A simple quantitative FT-IR approach for the study of a polymorphic transformation under crystallization slurry conditions.

The pharmaceutical compound (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine hydrochloride (denoted here as Compound X), has been found to crystallize in at least two polymorphic forms. Using only two frequencies (1009 and 1058 cm(-1)) in the infrared, a linear (R=0.998) calibration plot, consisting of the ratio of the peak absorbances plotted against polymorph concentration, was constructed. This plot allowed the quantification of binary mixtures of polymorphs ranging from <3 to approximately 100 wt% Form II in Form I. Spectra were acquired in transmission mode using mineral oil (Nujol) mull sample preparation, for reasons of compatibility with wet cake and slurry samples. The transformation of the less thermodynamically stable polymorph (Form II) to the more stable form (Form I), in stirred methyl isobutyl ketone (MIBK) slurries, was monitored spectroscopically as a function of time. Performing the experiment at various temperatures allowed the energy of activation for the process to be estimated (42 kJ/mol).

Crystallization↗

PubMed2001

Genetic dissection of the olfactory bulbs of mice: QTLs on four chromosomes modulate bulb size.

Olfaction is influenced by a complex mix of environmental and genetic factors that modulate the production, migration, and maturation of cells in the olfactory bulbs. In this study we analyzed effects of sex, age, body weight, and brain weight on olfactory bulb size in sexually mature mice. We then used regression corrected values (residuals) to map quantitative trait loci (QTLs) that selectively modulate bulb weight. This biometric analysis has relied on an F2 intercross between C57BL/6J (B6) and DBA/2J (D2) inbred strains and a large sample of 35 BXD recombinant inbred (RI) strains. Bilateral bulb weight in adult mice ranges from 10 to 30 mg. Half of this remarkable variation can be predicted from differences in brain weight, sex, body weight, and age. A 100-mg difference in brain weight is associated with a 4.4-mg difference in bulb weight. Bulbs gain in weight by 0.2 mg/week--a 1% increase that continues until at least 300 days of age. Males tend to have slightly larger bulbs than females. By combining data from both related crosses (F2 and RI) we identified four QTLs with selective effects on bulb size (genomewide p < .05). Bulb4a is located on chromosome 4 (Chr 4) and Bulb6a is located on Chr 6. Alleles inherited from B6 at both of these loci increase bulb weight by 0.5-1.0 mg. Bulb11a is located on proximal Chr 11 and Bulb17a is located on the proximal part of Chr 17. In contrast to the first two QTLs, B6 alleles at these two loci decrease bulb weight by 0.5-1.0 mg. Collectively, the four loci account for 20% of the phenotypic variance in bulb weight.

Alleles↗

PubMed2001

Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.

Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.

Animals↗

PubMed2001

Gastrointestinal stromal tumors: clinicopathological study of Chinese cases.

In the present study, we reviewed 73 Chinese cases of gastrointestinal stromal tumor (GIST), and analyzed factors in evaluating malignant potential, in particular focusing on Ki-67 index and p53 expression to determine whether these can be used as prognostic indicators in GIST. The p53 positive rate was 50.7% and it was significantly higher in malignant (25/35; 71.43%) than in benign cases (13/38; 34.21%). A Ki-67 labeling index of >10% was also significantly different between malignant (23/35; 65.71%) and benign cases (14/38; 36.84%). In the cases in which the patient died, 15/21 and 14/21 cases showed expression of p53 and Ki-67, respectively; both had a higher expression than in surviving cases. Comparing the cases positive for both Ki-67 and p53 with those positive for Ki-67 or p53 alone, and those negative for both Ki-67 and p53, the latter demonstrated the best prognosis. The study also indicated that the malignant potential of GIST is correlated with the mitotic index (> or =1/10 high-power fields; HPF), tumor size (> or =5 cm), high cellularity, tumor invasive growth, tumor location, tumor hemorrhage and tumor necrosis.

Adolescent↗

PubMed2001

Gene expression profiling in human fetal liver and identification of tissue- and developmental-stage-specific genes through compiled expression profiles and efficient cloning of full-length cDNAs.

Fetal liver intriguingly consists of hepatic parenchymal cells and hematopoietic stem/progenitor cells. Human fetal liver aged 22 wk of gestation (HFL22w) corresponds to the turning point between immigration and emigration of the hematopoietic system. To gain further molecular insight into its developmental and functional characteristics, HFL22w was studied by generating expressed sequence tags (ESTs) and by analyzing the compiled expression profiles of liver at different developmental stages. A total of 13,077 ESTs were sequenced from a 3'-directed cDNA library of HFL22w, and classified as follows: 5819 (44.5%) matched to known genes; 5460 (41.8%) exhibited no significant homology to known genes; and the remaining 1798 (13.7%) were genomic sequences of unknown function, mitochondrial genomic sequences, or repetitive sequences. Integration of ESTs of known human genes generated a profile including 1660 genes that could be divided into 15 gene categories according to their functions. Genes related to general housekeeping, ESTs associated with hematopoiesis, and liver-specific genes were highly expressed. Genes for signal transduction and those associated with diseases, abnormalities, or transcription regulation were also noticeably active. By comparing the expression profiles, we identified six gene groups that were associated with different developmental stages of human fetal liver, tumorigenesis, different physiological functions of Itoh cells against the other types of hepatic cells, and fetal hematopoiesis. The gene expression profile therefore reflected the unique functional characteristics of HFL22w remarkably. Meanwhile, 110 full-length cDNAs of novel genes were cloned and sequenced. These novel genes might contribute to our understanding of the unique functional characteristics of the human fetal liver at 22 wk.

Cloning, Molecular↗

PubMed2001

The domains of glycoprotein D required to block apoptosis depend on whether glycoprotein D is present in the virions carrying herpes simplex virus 1 genome lacking the gene encoding the glycoprotein.

An earlier report showed that viruses lacking the open reading frames encoding glycoproteins J and D but containing the glycoprotein D in their envelopes (gD-/+ stocks) and viruses lacking both the open reading frames and the glycoproteins in their envelopes (gD-/- stocks) induce apoptosis (G. Zhou, V. Galvan, G. Campadelli-Fiume, and B. Roizman, J. Virol. 74:11782-11791, 2000). Furthermore, apoptosis was blocked by delivery in trans of genes expressing glycoprotein D or J. Whereas gD-/- stocks attach but cannot initiate productive infection, gD-/+ stocks infect cells and produce gD-/- progeny virus. The difference in the infectivity of these two stocks suggested the possibility that the requirements for blocking apoptosis may be different. To test this hypothesis, we cloned into baculoviruses the entire wild-type glycoprotein D (Bac-gD-WT), the ectodomain only (Bac-gD-A), the ectodomain and the transmembrane domain (Bac-gD-B), the ectodomain and the cytoplasmic domain without the transmembrane domain (Bac-gD-C), or the transmembrane domain and the carboxyl-terminal cytoplasmic domain (Bac-gD-D). We report the following. Apoptosis induced by gD-/+ stocks was blocked by delivery in trans of recombinant baculovirus Bac-gD-WT, Bac-gD-A, Bac-gD-B, or Bac-gD-C but not of Bac-gD. Apoptosis induced by gD-/- stocks was blocked by Bac-gD-WT or by a mixture of Bac-gD-B and Bac-gD-D but not by any baculoviruses expressing truncated glycoprotein D alone or by the mixture of Bac-gD-A and Bac-gD-D. We conclude that the requirements to block apoptosis induced by the two virus stocks are different. The gD ectodomain is sufficient to block apoptosis induced by gD, whereas both the ectodomain and the cytoplasmic domain are required to block apoptosis induced by gD-/- stocks. The results indicate that in the case of gD-/- stocks, the transmembrane domain is required either to deliver the ectodomain to the appropriate intracellular compartment or to form multimeric constructs which virtually reconstitute gD through the interaction of transmembrane domains.

Animals↗

PubMed2001

Platelet monoamine oxidase B and plasma beta-phenylethylamine in Parkinson's disease.

OBJECTIVE: To evaluate the correlation between changes in platelet monoamine oxidase type B (MAO-B) activity and plasma beta-phenylethylamine (PEA) concentrations in patients with Parkinson's disease and controls. METHODS: Platelet MAO-B activity and plasma PEA were measured with gas chromatography-mass spectrometry (GC-MS) in patients with Parkinson's disease treated with levodopa (12 men and 12 women) or selegiline (three men and three women), and physically healthy subjects as a control group (10 men and 10 women). RESULTS: Platelet MAO-B activity was significantly higher in the Parkinson's disease group (mean 542 (SD 318) pmol/10(7) platelets/30 min) than in the control group (mean 349 (SD 307) pmol/10(7) platelets/30 min) (p<0.05). By contrast, the plasma PEA concentrations in patients with Parkinson's disease were significantly lower than in the control group (mean 532 (SD 243) pg/ml; 931 (SD 560) pg/ml) (p<0.01). The plasma PEA concentrations in patients with Parkinson's disease treated with selegiline were prominently higher than in patients with no selegiline treatment (p<0.001). There was a significantly negative correlation between platelet MAO-B activity and plasma PEA concentrations in patients (n=24, r=-0.466, p<0.001). CONCLUSIONS: The increase in platelet MAO-B activity and decrease in plasma PEA concentrations in patients with Parkinson's disease may be involved in the pathophysiological processes of the disease, and these changes are reversed by treatment with selegiline.

Aged↗

PubMed2001

Role of AMP-activated protein kinase in mechanism of metformin action.

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.

AMP-Activated Protein Kinases↗