Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition

Harwood, H. James

doi:10.1517/14728222.9.2.267

Cited by 111 publications

(118 citation statements)

References 81 publications

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“…Finally, ACC1 and its isoform ACC2 have become pharmaceutical targets, of concern for the inhibition of lipid accumulation and the prevention of hepatic steatosis and obesity (18,19). Present results showed that inactivation of ACC1could not protect the mice against diet-induced obesity or hepatic steatosis.…”

Section: Facc1ko Mice Show Decreased Osteoblastogenesismentioning

confidence: 71%

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aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues

Mao¹,

Yang²,

Gu³

et al. 2009

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

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Adipose tissue is one of the major sites for fatty acid synthesis and lipid storage. We generated adipose (fat)-specific ACC1 knockout (FACC1KO) mice using the aP2-Cre/loxP system. FACC1KO mice showed prenatal growth retardation; after weaning, however, their weight gain was comparable to that of wild-type (WT) mice on a normal diet. Under lipogenic conditions of fasting/re-feeding a fat-free diet, lipid accumulation in adipose tissues of FACC1KO mice was significantly decreased; this is consistent with a 50 -66% reduction in the ACC activity in these tissues compared with that of WT mice. Surprisingly, FACC1KO mice manifested skeletal growth retardation phenotype accompanied by decreased chondrocyte proliferation in the growth plate and lower trabecular bone density. In addition, there was about a 30% decrease in serum insulin-like growth factor I (IGF1), and while the serum leptin level was decreased by about 50%, it did not counteract the osteopenic effects of IGF1 on the bone. Fatty acid analyses of mutant bone lipids revealed relatively higher levels of C18:2n-6 and C18:3n-3 and lower levels of their elongation C20 homologs than that of WT cohorts, leading to lower levels of C20 homologs and bone development. Moreover, aP2-Cre-mediated ACC1 inactivation in bone tissue led to a decreased number of osteoblasts but not of osteoclasts. The downregulation of ACC1 on osteoblastogenesis may be the cause for the osteopenia phenotype of FACC1KO bone homeostasis.fat-specific ACC1 knockout ͉ osteoblastogenesis A cetyl-CoA carboxylase 1 (ACC1) catalyzes the synthesis of malonyl-CoA, the committed step toward de novo synthesis of long-chain fatty acids from acetyl-CoA (1). Deletion of ACC1 in mice resulted in embryonic lethality, indicating that fatty acid synthesis is essential for embryonic development (2). To understand the importance of de novo fatty acid synthesis and the role of ACC1 in adult mouse tissues, we generated tissue-specific knockout mice using the Cre-loxP system (3). Mice with liverspecific knockout of ACC1 (LACC1KO) fed normal chow did not exhibit any significant physiological differences from wildtype (WT) mice (3). But when fed a fat-free diet, they accumulated significantly less triglyceride (TG) in the liver compared with their WT cohorts. Although inactivation of ACC1 resulted in 70-75% lower ACC activity in the liver, it did not affect either glucose homeostasis or hepatic fatty acid oxidation (3). When the LACC1KO mice were fed a fat-free diet for 10 days, there was an upregulation of PPAR␥ and several lipogenic enzymes in the liver, including a 2-fold increase in fatty acid synthase (FAS) mRNA, protein, and activity. However, syntheses of fatty acid and TG were reduced significantly. Upregulated ACC2 gene expression did not compensate for the loss of ACC1 function, an observation similar to that noted in Acc2 Ϫ/Ϫ mice in which the cytosolic ACC1 did not compensate for the mitochondrialassociated ACC2 and its product malonyl-CoA (4).Adipose tissues are active lipogenic and fat storage tissues,...

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Section: Facc1ko Mice Show Decreased Osteoblastogenesismentioning

confidence: 71%

“…ACC1 has been thought to be a good target for the drug treatment of obesity (18,19). To test whether the disruption of ACC1 in adipose tissues would inhibit diet-induced obesity, 2-month-old male mice were fed a high fat/high carbohydrate (HF/HC) diet for 10 weeks.…”

Section: Facc1ko Mice Show Decreased Osteoblastogenesismentioning

confidence: 99%

aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues

Mao¹,

Yang²,

Gu³

et al. 2009

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

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“…Furthermore, these changes were not associated with any changes in plasma concentrations of IL-6, TNF-␣, adiponectin, or resistin, suggesting that these adipocytokines were not involved in mediating insulin resistance in this mouse model. Several pharmacological attempts have been made to inhibit ACC (40). Major difficulties have included problems in generating ACC isoform specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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

Choi¹,

Savage²,

Abu-Elheiga

et al. 2007

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

282

232

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Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2 ؊/؊ and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulinstimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2 ؊/؊ and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2 ؊/؊ mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2 ؊/؊ mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC activity in muscle and PKC activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2 ؊/؊ mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes. diet-induced obesity prevention ͉ intracellular diacylglycerol ͉ increased fat oxidation ͉ insulin resistance prevention

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“…Thus, hyperinsulinemia and/or glucocorticoid excess might cause accumulation of triglyceride partly via the effects of the two hormones on ACC1/2 expression. In this context, pharmacological inhibition of ACC might be a promising therapeutic tool for the prevention of abdominal obesity frequently observed in the metabolic syndrome [36,37].…”

Section: The Effects Of Lxrα/β Co-expression On the Transcriptional Amentioning

confidence: 99%

Hormonal Regulation of Acetyl-CoA Carboxylase Isoenzyme Gene Transcription

et al. 2010

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Glucose is catalyzed via the glycolytic pathway to pyruvate and then oxidized to generate ATP. However, excess glucose is converted to fatty acid via the lipogenic pathway by a number of enzymes including acetyl-CoA carboxylase (ACC) [1]. Short-term glucose/lipid metabolism is regulated by allosteric changes of the regulatory enzymes, whereas long-term metabolism is mediated by changes in the transcription of each enzyme gene. Indeed, recent in vivo studies show that the amounts of mRNAs for the enzymes change dynamically in response to both fasting and feeding [2,3]. Furthermore, insulin and glucocorticoid, the two major hormones harboring a potent an- Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Japan Abstract. Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. Acetyl-CoA, an intermediate product of glycolysis, is supplied for fatty acid synthesis when carbohydrate intake is sufficient. Acetyl-CoA carboxylase (ACC), consisting of two isoenzymes ACC1 and ACC2, mediates the conversion from acetyl-CoA to malonyl-CoA, and thus plays a key role for the regulation of lipogenesis. In this study, we surveyed the effects of glucocorticoid and insulin on the transcriptional activity of the alternative promoters of ACCs (PI-PIII for ACC1, and PI and PII for ACC2) using the Hepg2 human hepatocyte cell line in vitro. We also examined the roles of the insulin and/or glucose-regulated transcriptional factor(s) such as SReBP1c, LXRα/β, and ChReBP on each promoter of the ACC genes. We found that both insulin and glucocorticoid had potent positive effects on all the promoters examined, and additive effects of both hormones were recognized in ACC1 PI and ACC2 PI. Furthermore, a representative insulin-responsive transcription factor SReBP1c showed significant stimulatory effects on all the promoters of ACC genes, among which those on ACC1 PIII and ACC2 PI were most prominent. On the other hand, the effect of LXRα was rather selective; it showed a marked stimulatory effect only on ACC1 PII. LXRβ and ChReBP had minimal, if any, effects on some of the promoters. Altogether, our data suggest that insulin and glucocorticoid have positive effects on both ACC1 and ACC2 gene transcription. SReBP1c might be a master regulator of the expression of both genes regardless of the promoter utilized, whereas LXRα seems to play a promoter-specific role. Since ACC1 facilitates lipogenesis by stimulating fatty acid synthesis and ACC2 inhibits lipolysis, both insulin and glucocorticoid seem to play an important role in the pathogenesis of obesity and/or hepatic steatosis.

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Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition

Cited by 111 publications

References 81 publications

aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues

aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues

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

Hormonal Regulation of Acetyl-CoA Carboxylase Isoenzyme Gene Transcription

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