Genetic downregulation of AMPK-α isoforms uncovers the mechanism by which metformin decreases FA uptake and oxidation in skeletal muscle cells

Author:

Bogachus Lindsey D.12,Turcotte Lorraine P.12

Affiliation:

1. Department of Biological Sciences and

2. Department of Kinesiology, College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California

Abstract

Metformin is known to improve insulin sensitivity in part via a rise in AMP-activated protein kinase (AMPK) activity and alterations in muscle metabolism. However, a full understanding of how metformin alters AMPK-α1vs. AMPK-α2activation remains unknown. To study this question, L6 skeletal muscle cells were treated with or without RNAi oligonucleotide sequences to downregulate AMPK-α1or AMPK-α2protein expression and incubated with or without 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or metformin and/or insulin. In contrast to AICAR, which preferentially activated AMPK-α2, metformin preferentially activated AMPK-α1in 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 with no change in acetyl-CoA carboxylase (ACC) phosphorylation ( P > 0.05). AICAR and metformin similarly increased ( P < 0.05) nuclear silent mating-type information regulator 2 homolog 1 (SIRT1) activity. Downregulation of AMPK-α1completely prevented the metformin-induced reduction in palmitate uptake and oxidation but only partially reduced the metformin-induced increase in glucose uptake. Downregulation of AMPK-α2had no effect on metformin-induced glucose uptake, palmitate uptake, and oxidation. The increase in SIRT1 activity induced by metformin was not affected by downregulation of either AMPK-α1or AMPK-α2. Our data indicate that, in muscle cells, the inhibitory effects of metformin on fatty acid metabolism occur via preferential phosphorylation of AMPK-α1, and the data indicate that cross talk between AMPK and SIRT1 does not favor either AMPK isozyme.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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