Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice

Glund, Stephan; Schoelch, Corinna; Thomas, Leo H.; Niessen, Heiko G.; Stiller, Detlef; Roth, Gerald J.; Neubauer, Heike

doi:10.1007/s00125-012-2554-9

Cited by 33 publications

(20 citation statements)

References 40 publications

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“…Furthermore, ND-630 did not increase hyperglycemia in prediabetic ZDF rats relative to vehicle-treated animals and did not exacerbate the hyperglycemia of overtly diabetic animals but instead improved GSIS and reduced HbA1c levels in these animals. This effect, which also has been reported in db/db mice treated with (S)-9c (30), is suggestive of β-cell preservation.…”

Section: Discussionsupporting

confidence: 82%

“…A large number of isozyme-nonselective ACC inhibitors have been identified that interfere directly with ACC catalysis through interaction within the CT domain of the enzyme and have been shown to be potent in vitro and efficacious in vivo (1,9,19,(27)(28)(29)(30). Indeed, in early clinical trials one such inhibitor recently has been shown to reduce FASyn and to stimulate FAOxn after a single oral dose (29).…”

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confidence: 99%

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Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

Harriman¹,

Greenwood

Bhat

et al. 2016

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

239

188

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Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein–protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

Harriman¹,

Greenwood

Bhat

et al. 2016

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

239

188

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“…However, knockout of genes that control important metabolic regulators may lead to compensatory antenatal changes affecting appetite; thus, the knockout does not always have the same effects as inhibition of the corresponding metabolic regulators in adults. For example, deletion of the gene for acetyl CoA carboxylase 2 did not improve glucose homeostasis in db / db mice , but a small‐molecule acetyl CoA carboxylase 2 inhibitor has been reported to do so . Acetyl CoA carboxylase 2 is a key regulator of fatty acid oxidation, but adaptation during fetal development and/or early life may compensate for reduced hunger signalling to the brain in acetyl CoA carboxylase 2 null mice.…”

Section: The Role Of Cannabinoid Receptors In Fatty Livermentioning

confidence: 99%

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake

Cooper

Regnell

2013

Brit J Clinical Pharma

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The cannabinoid 1 receptor (CB1R) has a well-established role in appetite regulation. Central CB1R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side-effects. The CB1R is also expressed peripherally, where its effects include promotion of liver fat accumulation, which consumes ATP. Type 2 diabetes in obese subjects is linked to excess liver fat, whilst there is a negative correlation between hepatic ATP content and insulin resistance. A decreased hepatic ATP/AMP ratio increases food intake by signals via the vagus nerve to the brain. The hepatic cannabinoid system is highly upregulated in obesity, and the effects of hepatic CB1R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blockade of hepatic CB1Rs could contribute significantly to the weight-reducing and insulin-sensitizing effects of CB1R antagonists. Additionally, upregulation of the hepatic CB1R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis. Peripheral CB1R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB1Rs are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB1R antagonists may be effective at reducing hepatic steatosis, insulin resistance and bodyweight in obese, diabetic patients, with far fewer side-effects than first-generation CB1R antagonists. Additionally, such compounds may be effective in treating inflammatory liver disease, such as non-alcoholic steatohepatitis, reducing the likelihood of disease progression to cirrhosis or cancer. Hepatic energy state and its effects on food intakeThe cellular energy state is defined by adenine nucleotide levels. Healthy cells maintain a ratio of ATP to ADP of the order of 10:1. Cellular concentrations of ADP typically remain constant, while ATP and AMP levels deviate in reciprocal directions [1].Hepatic energy state influences food intake [2, 3]. For instance, infusion of various lipids and carbohydrates into the hepatic portal vein of rodents was found to suppress food intake more effectively than administration of the same nutrients into the jugular vein [2]. Supporting results were found when injecting the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) into the portal vein. In the liver, 2,5-AM is phosphorylated at the 1 and 6 positions, but not metabolized further, thus lowering the levels of free intracellular phosphates, which reduces the generation of ATP, whilst increasing its degradation by disinhibiting adenosine deaminase. The net result is a lower hepatocellular ATP concentration, which increases feeding [4]. Pretreatment with sodium phosphate prevents the decrease in liver ATP levels and the increase in feeding [5]. Administration of the amino-acid analogue L-ethionin...

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“…Insulin resistance, one of the hallmarks of metabolic syndrome, is strongly associated with elevated levels of free FAs [3]. It has been argued that an imbalance between cellular FA uptake and oxidation leads to accumulation of FAs and other lipid molecules in the cytosol, which in turn causes insulin resistance [4], [5]. Others showed that a functioning acyl-CoA uptake into mitochondria is needed to develop insulin resistance, leading to the hypothesis that intermediates of FA β-oxidation are part of the problem [6].…”

Section: Introductionmentioning

confidence: 99%

Biochemical Competition Makes Fatty-Acid β-Oxidation Vulnerable to Substrate Overload

et al. 2013

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Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD+]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.

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Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice

Abstract: In conclusion, the ACC2-selective inhibitor (S)-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus.

Cited by 33 publications

References 40 publications

Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake

Biochemical Competition Makes Fatty-Acid β-Oxidation Vulnerable to Substrate Overload

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