Genetic downregulation of AMPK{alpha} isoforms uncovers the mechanism by which metformin decreases FA uptake and oxidation in skeletal muscle cells.
Summary of "Genetic downregulation of AMPK{alpha} isoforms uncovers the mechanism by which metformin decreases FA uptake and oxidation in skeletal muscle cells."
Metformin is known to improve insulin sensitivity in part via a rise in AMPK activity and alterations in muscle metabolism. However, a full understanding of how metformin alters AMPKα(1) vs. AMPKα(2) activation remains unknown. To study this question, L6 skeletal muscle cells were treated ± RNAi oligonucleotide sequences to downregulate AMPKα(1) or AMPKα(2) protein expression and incubated ± AICAR or metformin and/or insulin. In contrast to AICAR which preferentially activated AMPKα(2), metformin preferentially activated AMPKα(1) in a dose- and time-dependent manner. Metformin increased (P<0.05) glucose uptake and plasma membrane (PM) Glut4 in a dose- and time-dependent manner. Metformin significantly reduced palmitate uptake (P<0.05) and oxidation (P<0.05) and this was accompanied by a similar decrease (P<0.05) in PM CD36 content but no change in Acetyl CoA Carboxylase (ACC) phosphorylation (P>0.05). AICAR and metformin similarly increased (P<0.05) nuclear SIRT1 activity. Downregulation of AMPKα(1) completely prevented the metformin-induced reduction palmitate uptake and oxidation but only partially reduced the metformin-induced increase in glucose uptake. Downregulation of AMPKα(2) had no effect on metformin-induced glucose uptake, and palmitate uptake and oxidation. The increase in SIRT1 activity induced by metformin was not affected by downregulation of either AMPKα(1) or AMPKα(2). Our data indicate that, in muscle cells, the inhibitory effects of metformin on FA metabolism occur via preferential phosphorylation of AMPKα(1) and the data indicate that cross-talk between AMPK and SIRT1 does not favor either AMPK isozyme.
Affiliation
1University of Southern California.
Journal Details
This article was published in the following journal.
Name: American journal of physiology. Cell physiology
ISSN: 1522-1563
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20844250
- DOI: http://dx.doi.org/10.1152/ajpcell.00279.2010
Medical and Biotech [MESH] Definitions
Alpha-mannosidase
An enzyme that catalyzes the HYDROLYSIS of terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. The enzyme plays a role in the processing of newly formed N-glycans and in degradation of mature GLYCOPROTEINS. There are multiple isoforms of alpha-mannosidase, each having its own specific cellular location and pH optimum. Defects in the lysosomal form of the enzyme results in a buildup of mannoside intermediate metabolites and the disease ALPHA-MANNOSIDOSIS.
Integrin Alpha3
An integrin alpha subunit that occurs as alternatively spliced isoforms. The isoforms are differentially expressed in specific cell types and at specific developmental stages. Integrin alpha3 combines with INTEGRIN BETA1 to form INTEGRIN ALPHA3BETA1 which is a heterodimer found primarily in epithelial cells.
Recombination, Genetic
Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.
Genetics, Population
The discipline studying genetic composition of populations and effects of factors such as GENETIC SELECTION, population size, MUTATION, migration, and GENETIC DRIFT on the frequencies of various GENOTYPES and PHENOTYPES using a variety of GENETIC TECHNIQUES.
Integrin Alpha Chains
The alpha subunits of integrin heterodimers (INTEGRINS), which mediate ligand specificity. There are approximately 18 different alpha chains, exhibiting great sequence diversity; several chains are also spliced into alternative isoforms. They possess a long extracellular portion (1200 amino acids) containing a MIDAS (metal ion-dependent adhesion site) motif, and seven 60-amino acid tandem repeats, the last 4 of which form EF HAND MOTIFS. The intracellular portion is short with the exception of INTEGRIN ALPHA4.
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