Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue

Abstract

Synthesis of fatty acid (FA) in adipose tissue requires cooperation of mitochondrial and cytoplasmic enzymes. Mitochondria are required for the production of ATP and they also support the formation of acetyl-CoA and NADPH in cytoplasm. Since cellular levels of all these metabolites depend on the efficiency of mitochondrial energy conversion, mitochondrial proton leak via uncoupling proteins (UCPs) could modulate FA synthesis. In 3T3-L1 adipocytes, 2,4-dinitrophenol depressed the synthesis of FA 4-fold while increasing FA oxidation 1. 5-fold and the production of lactate 14-fold. Inhibition of FA synthesis in 3T3-L1 adipocytes was proportional to the decrease in mitochondrial membrane potential. FA synthesis from D-[U-(14)C] glucose was reduced up to fourfold by ectopic UCP1 in the white fat of transgenic aP2-Ucp1 mice, reflecting the magnitude of UCP1 expression in different fat depots and the reduction of adiposity. Transcript levels for lipogenic enzymes were lower in the white fat of the transgenic mice than in the control animals. Our results show that uncoupling of oxidative phosphorylation depresses FA synthesis in white fat. Reduction of adiposity via mitochondrial uncoupling in white fat not only reflects increased energy expenditure, but also decreased in situ lipogenesis.

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

“…When (post)prandial plasma levels of NEFA and triacylglycerol (TG) exceed the storage capacity of WAT [1], other tissues including the liver and muscle become overloaded with lipids, which results in insulin resistance, the key event in the pathophysiology of metabolic syndrome [2]. The important role of WAT in energy homeostasis is underscored by the findings that WAT is one of the key organs affected by calorie restriction, the most effective strategy to prolong a healthy life in several species [3], and by the fact that accumulation of body fat can be reduced through upregulation of lipid catabolism in WAT [4][5][6][7][8][9][10]. The metabolism and secretory functions of WAT are also modulated by longchain (LC) n-3 polyunsaturated fatty acids (PUFA), namely eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3), which exert numerous beneficial effects on health, including improvements in lipid metabolism and prevention of obesity and diabetes [11], while decreasing the rate of fatal coronary heart disease in diabetic patients who have had a myocardial infarction [12].…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…Furthermore, expression of ectopic UCP1 resulted in reduced expression of genes characteristic of differentiated energy-storing adipocytes, such as peroxisome proliferator-activated receptor gamma (PPARc) and aP2 , in analogy with the induction of ''fat burning adipocytes'' in response to leptin treatment in rats (Zhou et al 1999). In accordance, mitochondrial uncoupling in adipocytes in vitro led to lower intracellular ATP concentrations (Yamada et al 2006;Si et al 2009), up-regulation of glycolysis and mitochondrial biogenesis, and down-regulation of energyconsuming pathways such as fatty acid synthesis (Rossmeisl et al 2000;Si et al 2009;Senocak et al 2007), while lactate production was increased (Rossmeisl et al 2000; ) N D Decreased (Ishigaki et al 2005) Mitochondrial biogenesis and/or content Increased (Rossmeisl et al 2002) Content decreased (Han et al 2004) N D Mitochondrial ROS production ND Reduced (Keipert et al 2010) N D Cellular ATP levels Decreased Yamada et al 2006); increased AMP/ATP ratio Unchanged (Li et al 2000) or decreased (Li et al 2000;Couplan et al 2002;Han et al 2004 Rossmeisl et al, unpublished) suggested an upregulation of lipid catabolism in SM of high-fat diet-fed mice in response to the transgenic UCP1 expression in WAT, which is also associated with hypolipidemic effects, especially under fasted conditions. The effect of UCP1 expression on SM phenotype was studied in detail by Couplan et al (2002), who reported a fiber type switch from fast glycolytic fibers to slow oxidative fibers in gastrocnemius and plantaris muscle accompanied by a reduced muscle mass.…”

“…That mitochondrial uncoupling in WAT could reduce obesity was found in 1995 by Kopecky et al (1995) using aP2-Ucp1 transgenic mice and explored systematically later on (Kopecky et al 1996a, b;Stefl et al 1998;Baumruk et al 1999;Rossmeisl et al 2000Rossmeisl et al , 2002Rossmeisl et al , 2005Flachs et al 2002;Matejkova et al 2004). In these mice, the fatspecific aP2 promoter was used to drive expression of UCP1 from the whole genomic DNA sequence, resulting in enhanced expression of UCP1 in both WAT and BAT of mice with C57BL/6 J background.…”

“…The activity of a1 AMPK complex, a more abundant form of AMPK in WAT as compared with a2 AMPK (Daval et al 2005), was increased more in subcutaneous than in epididymal WAT , reflecting the UCP1 content in WAT and the change in the cellular AMP/ATP ratio (Rossmeisl et al 2002). The activation of AMPK in response to mitochondrial uncoupling could explain fat depot-specific depression of lipogenesis (Rossmeisl et al 2000) and lipolysis , increase in fatty acid oxidation ) and mitochondrial content (Rossmeisl et al 2002), as well as down-regulation of PPARc and its target gene aP2, documenting suppression of the adipogenic potential of the tissue ). Thus, AMPK possibly represents the major regulatory intracellular pathway responsible for the array of metabolic changes induced by UCP1 in white adipocytes.…”

“…In addition to the inhibitory effect of AMPK on lipolysis (see ''Role of AMPK in energy metabolism and glucose homeostasis'' section), the suppression of lipolytic activity could be augmented by lactate (Ahmed et al 2010) produced at a higher rate in response to mitochondrial uncoupling (Rossmeisl et al 2000;Si et al 2009), while increased in situ fatty acid oxidation would limit further release of fatty acids into circulation. The inhibition of de novo fatty acid synthesis in WAT of aP2-Ucp1 mice could also reflect changes in the extramitochondrial acetyl-CoA and NADPH levels (Rossmeisl et al 2000). In fact, both the activation of fatty acid oxidation and inhibition of lipogenesis by AMPK in response to mitochondrial uncoupling would lower fat accumulation.…”