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Fatty acids revert the inhibition of respiration caused by the antidiabetic drug metformin to facilitate their mitochondrial β-oxidation

AuthorsGonzález-Barroso, M. Mar ; Anedda, Andrea ; Gallardo-Vara, Eunate ; Redondo-Horcajo, Mariano ; Rodríguez-Sánchez, Leonor ; Rial, Eduardo
fatty acid oxidation
Issue DateOct-2012
CitationBBA - Bioenergetics, 1817 (10) : 1768-1775 (2012)
AbstractWhile metformin has been widely used to treat type 2 diabetes for the last fifty years, its mode of action remains unclear. Hence, we investigated the short-term alterations in energy metabolism caused by metformin administration in 3T3-L1 adipocytes. We found that metformin inhibited mitochondrial respiration, although ATP levels remained constant as the decrease in mitochondrial production was compensated by an increase in glycolysis. While AMP/ATP ratios were unaffected by metformin, phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase augmented. The inhibition of respiration provoked a rapid and sustained increase in superoxide levels, despite the increase in UCP2 and superoxide dismutase activity. The inhibition of respiration was rapidly reversed by fatty acids and thus respiration was lower in treated cells in the presence of pyruvate and glucose while rates were identical to control cells when palmitate was the substrate. We conclude that metformin reversibly inhibits mitochondrial respiration, it rapidly activates AMPK without altering the energy charge, and it inhibits fatty acid synthesis. Mitochondrial β-oxidation is facilitated by reversing the inhibition of complex I and, presumably, by releasing the inhibition of carnitine palmitoyltransferase. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012)
Description8 páginas, 4 figuras -- PAGS nros. 1768-1775
Publisher version (URL)http://dx.doi.org/10.1016/j.bbabio.2012.02.019
Appears in Collections:(CIB) Artículos
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