Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Choi, Cheol Soo; Savage, David B.; Abu-Elheiga, Lutfi; Liu, Zhenxiang; Kim, Sheene; Kulkarni, Ameya; Distefano, Alberto; Hwang, Yu-Jin; Reznick, Richard M.; Codella, Roberto; Zhang, Dongyan; Cline, Gary W.; Wakil, Salih J.; Shulman, Gerald I.

doi:10.1073/pnas.0706794104

Cited by 282 publications

(252 citation statements)

References 51 publications

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“…Consistent with our hypothesis of lipid metabolites inducing insulin resistance (6,9,10,(17)(18)(19)(20), muscle triglyceride, lysophosphatidic acid, and long-chain acyl CoAs were markedly increased in MPGC-1␣ TG mice fed a high-fat diet compared with WT mice (Fig. 3 A, C, and D).…”

Section: Mechanism For Increased Insulin Resistance In Skeletal Musclsupporting

confidence: 76%

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Choi

Befroy

Codella

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣ has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1␣ in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1␣ expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using 31 P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1␣ in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an Ϸ60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1␣ expression on whole-body energy expenditure, and PGC-1␣ transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKC , decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.diacylglycerol ͉ fatty acid oxidation ͉ insulin resistance ͉ magnetic resonance spectroscopy ͉ mitochondria

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Section: Mechanism For Increased Insulin Resistance In Skeletal Musclsupporting

confidence: 76%

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Choi

Befroy

Codella

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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262

264

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“…This may prevent the build-up of ROS or products of incomplete β-oxidation, such as specific acylcarnitine esters, which have been linked to insulin resistance [33,34]. A reduction in β-oxidation in association with improved insulin sensitivity has been described predominantly in muscle [31,34] and is in direct contrast to other findings indicating a positive role for β-oxidation [35][36][37]. However, we now suggest the reduction we have observed may be beneficial in the liver under conditions of short-term lipid oversupply, especially as we observed a decrease in ROS generation in lipid-treated Prkce −/− hepatocytes.…”

Section: Discussioncontrasting

confidence: 53%

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

et al. 2011

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Aims/hypothesis We examined the time-dependent effects of deletion of the gene encoding protein kinase C epsilon (Prkce) on glucose homeostasis, insulin secretion and hepatic lipid metabolism in fat-fed mice. Methods Prkce −/− and wild-type (WT) mice were fed a high-fat diet for 1 to 16 weeks and subjected to i.p. glucose tolerance tests (ipGTT) and indirect calorimetry. We also investigated gene expression and protein levels by RT-PCR, quantitative protein profiling (isobaric tag for relative and absolute quantification; iTRAQ) and immunoblotting. Lipid levels, mitochondrial oxidative capacity and lipid metabolism were assessed in liver and primary hepatocytes.Results While fat-fed WT mice became glucose intolerant after 1 week, Prkce −/− mice exhibited normal glucose and insulin levels. iTRAQ suggested differences in lipid metabolism and oxidative phosphorylation between fat-fed WT and Prkce −/− animals. Liver triacylglycerols were increased in fat-fed Prkce −/− mice, resulting from altered lipid partitioning which promoted esterification of fatty acids in hepatocytes. In WT mice, fat feeding elevated oxygen consumption in vivo and in isolated liver mitochondria, but these increases were not seen in Prkce −/− mice. Prkce −/− hepatocytes also exhibited reduced production of reactive oxygen species (ROS) in the presence of palmitate. After 16 weeks of fat feeding, however, the improved glucose tolerance in fat-fed Prkce −/− mice was instead associated with increased insulin secretion during ipGTT, as we have previously reported. Conclusions/interpretation Prkce deletion ameliorates dietinduced glucose intolerance via two temporally distinct phenotypes. Protection against insulin resistance is associated with changes in hepatic lipid partitioning, which may reduce the acute inhibitory effects of fatty acid catabolism, such as ROS generation. In the longer term, enhancement of glucose-stimulated insulin secretion prevails.

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“…The method that enables versatile studies on ACCase genes functions in living organims relies on transgenic mouse lines with knock-out genes. A systemic ACC2 knock-out was reported to cause continuous fatty acids oxidation, reduced hepatic and body fat mass and an increase in energy expenditure, which was associated with reduced skeletal and cardiac muscle malonyl-coenzyme A and reduced susceptibility for diet-induced obesity and diabetes (Abu-Elheiga et al, 2001;Abu-Elheiga et al, 2003;Choi et al, 2007). Recently a new mouse line has been generated, which enabled conditional deletion of ACC2 gene from skeletal muscles -the predominant site of this gene expression.…”

Section: Human Accase As Target In Diseases Treatmentmentioning

confidence: 99%

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Podkowiński¹,

Tworak²

2011

bta

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Acetyl-CoA carboxylase catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. This reaction constitutes the first committed step of fatty acid synthesis in most organisms, while its product also serves as a universal precursor for various other high-value compounds. The important regulatory and rate-limiting role of acetyl-CoA carboxylase makes this enzyme a powerful tool in a variety of biotechnological and medical projects. This review presents the current knowledge on structural and functional features of the enzyme and focuses on its divergent applications. Different metabolic engineering attempts that lead to the production of various compounds, such as fatty acids, polyketides or flavonoids, are presented and their advantages and limitations discussed. The importance of studies on acetyl-CoA carboxylase activity for design and development of new herbicides and antibiotics as well as for medical intervention is also highlighted. Acetyl-coenzyme A carboxylase -enzyme architecture, biochemistry and its role in cell physiologyA variety of biotechnological projects targeted to modulate acetyl-coenzyme A carboxylase activity in bacteria, plants and humans have been proposed and experimentally tested. Here, we would like to present a comprehensive review of these strategies together with a survey of the potential of acetyl-CoA carboxylase for biotechnology.Acetyl-coenzyme A carboxylase (ACC, E.C.6.4.1.2), recognized as an essential enzyme for all Eukaryotes and the majority of Bacteria, is responsible for carboxylation of acetyl-CoA that results in malonyl-coenzyme A formation (Fig. 1). Malonyl-CoA is a major building block for compounds such as fatty acids, polyketides and flavonoids -important components for cell growth, as well as for food, pharmaceuticals and energy production.The malonyl-CoA synthesis consists of two half-reactions (Nikolau et al., 2003). The first one, adenosine triphosphate-dependent carboxylation of biotin prosthetic group covalently bound to a module named biotin carboxyl carrier protein (BCCP), is catalyzed by ACCase segment of biotin carboxylase activity (BC) (Fig. 2). This reaction is immediately followed by the second half-re action: the transfer of a carboxyl group from carboxylated biotin to acetyl-CoA, resulting in malonyl-CoA formation. Carboxyl transferase (CT) is a module that catalyzes the second reaction and provides the required specificity in recognition of the carboxyl acceptor (acetyl-CoA). The ACCase model usually presents BCCP, a module with covalently attached biotin, as a beam responsible for biotin dislocation between two active centers -one with BT and the other with CT activity. The three (Fig. 3). The prokaryotic and eukaryotic types of ACCases are evolutionary related and the phylogeny of the modules provides some hints about their cenancestor, a split between Archaea and Bacteria, and arising of Eukaryota (Lombard and Moreira, 2011).Phylogeny is out of scope of this manuscript, but acetyl-coenzyme A carboxylases from various organisms representing v...

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Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Cited by 282 publications

References 51 publications

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

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