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

Abstract

While 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).

Metformin and Pancreatic Cancer Metabolism

“…Adipocytes treated with palmitate complexed to albumin in the presence of carnitine had comparable oxygen consumption rates when compared to control. These results indicate that the metformin-induced inhibition of respiration can be reversed by the addition of fatty acids, which led the authors to conclude that the mechanism of action of metformin may be linked to fatty acid metabolism [19]. Although indirect, this article presented a link between metformin and its effects on lipid metabolism or vice versa.…”

“…The levels of additional mevalonate (MVA) pathway genes were also significantly correlated with poor prognosis of breast cancer patients, suggesting the entire pathway may be deregulated in these cases [97]. It is interesting to note that the metformin-induced inhibition of respiration is blocked by the addition of palmitate in 3T3-L1 adipocytes [19]. Adipocytes treated with palmitate complexed to albumin in the presence of carnitine had comparable oxygen consumption rates when compared to control.…”

“…We also discuss in depth the anti-cancer mechanisms of action of metformin in the context of lipid metabolism as reported in numerous models. These include metformin's ability to increase fatty acid β-oxidation in adipocytes [19] and its ability to inhibit hepatic lipogenesis [2]. As shown by numerous studies [20][21][22][23], metformin also possesses antilipogenic properties, potentially limiting this critical metabolic pathway that confers cancer pancreatic cell survival advantage.…”

Involvement of mTOR and Regulation by AMPK in Early Iodine Deficiency-Induced Thyroid Microvascular Activation

“…This in turn increases the activity of AMPK (47,48), which can then activate the HIF-VEGF pathway (49,50). Alternatively, and besides the effect of metformin on the AMP to ATP ratio, the inhibition of the mitochondrial complex 1 by metformin may also result in increased ROS and nitrogen species production, which also activates AMPK (51). In addition to their action on AMPK, ROS produced by mitochondria may, by themselves, directly induce the HIF-1-VEGF pathway (52).…”

Glucagon Regulation of Oxidative Phosphorylation Requires an Increase in Matrix Adenine Nucleotide Content through Ca2+ Activation of the Mitochondrial ATP-Mg/Pi Carrier SCaMC-3

“…To this end, mitochondrial samples were treated with 10% HClO 4 overnight, neutralized using K 2 CO 3 , kept on ice 10 min, and then at Ϫ80°C for 1 h to allow precipitation of HClO 4 . Extracts were centrifuged and 50 l of the supernatants were injected for AdN determination (21). To determine the identity of each peak and quantify the amount of the species of interest, standard curves were constructed by plotting peak heights versus known concentrations of ATP, ADP, and AMP (22).…”