Mechanism by which arylamine
            <i>N</i>
            -acetyltransferase 1 ablation causes insulin resistance in mice

Camporez, João Paulo; Wang, Yong Liang; Faarkrog, Kasper; Chukijrungroat, Natsasi; Petersen, Kitt Falk; Shulman, Gerald I.

doi:10.1073/pnas.1716990115

Cited by 54 publications

(56 citation statements)

References 43 publications

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“…Nat1 knockdown in 3T3-L1 cells with sh-RNA decreased both basal respiration as well as reserve respiratory capacity. A similar finding was reported for hepatocytes isolated from Nat1 null mice (Camporez et al, 2017), suggesting that human NAT2 (or mouse Nat1) is important for mitochondrial function. Previously, we reported that deletion of NAT1 in various human cells including MDA-MB-231 cells, using CRISPR/Cas9 technology decreased oxidative phosphorylation (Lichter et al, 2017).…”

Section: Introductionsupporting

confidence: 83%

“…The changes in mitochondrial function in the MDA-MB-231 and HT-29 cells are similar to those reported in murine cells following Nat1 knockout (Camporez et al, 2017;Chennamsetty et al, 2016). Nat1 is the murine homolog of human NAT2, not NAT1, so the similarity in responses following gene deletion was unexpected.…”

Section: Discussionsupporting

confidence: 66%

“…Recently, single nucleotide polymorphisms in the NAT2 gene, which result in a slow acetylator phenotype, were shown to be associated with insulin resistance (Knowles et al, 2015). Moreover, deletion of the murine homolog of human NAT2 (Nat1) recapitulated the insulin resistance phenotype (Camporez et al, 2017), increased mitochondrial dysfunction and the production of reactive oxygen species (ROS) (Chennamsetty et al, 2016). Nat1 knockdown in 3T3-L1 cells with sh-RNA decreased both basal respiration as well as reserve respiratory capacity.…”

Section: Introductionmentioning

confidence: 99%

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Loss of human arylamine N-acetyltransferase I regulates mitochondrial function by inhibition of the pyruvate dehydrogenase complex

Wang

Minchin

Essebier

et al. 2019

The International Journal of Biochemistry & Cell Biology

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Human arylamine N-acetyltransferase 1 (NAT1) has been widely reported to affect cancer cell growth and survival and recent studies suggest it may alter cell metabolism. In this study, the effects of NAT1 deletion on mitochondrial function was examined in 2 human cell lines, breast carcinoma MDA-MB-231 and colon carcinoma HT-29 cells. Using a Seahorse XFe96 Flux Analyzer, NAT1 deletion was shown to decrease oxidative phosphorylation with a significant loss in respiratory reserve capacity in both cell lines. There also was a decrease in glycolysis without a change in glucose uptake. The changes in mitochondrial function was due to a decrease in pyruvate dehydrogenase activity, which could be reversed with the pyruvate dehydrogenase kinase inhibitor dichloroacetate. In the MDA-MB-231 and HT-29 cells, pyruvate dehydrogenase activity was attenuated either by an increase in phosphorylation or a decrease in total protein expression. These results may help explain some of the cellular events that have been reported recently in cell and animal models of NAT1 deficiency.

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Section: Introductionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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Loss of human arylamine N-acetyltransferase I regulates mitochondrial function by inhibition of the pyruvate dehydrogenase complex

Wang

Minchin

Essebier

et al. 2019

The International Journal of Biochemistry & Cell Biology

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“…Interestingly it has been shown, using Nat2 KO mice, that mouse NAT2/human NAT1 play a role in folate metabolism through acetylation of folate metabolite para‐aminobenzoylglutamate . Phenotype differences observed between our study and the above mentioned studies may also rise from environmental differences in particular in animal diets.…”

Section: Resultsmentioning

confidence: 43%

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

et al. 2019

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Recent studies have revealed a possible link between the activities of polymorphic arylamine N‐acetyltransferases (NATs) and energy metabolism. We used a Nat1/Nat2 double knockout (KO) mouse model to demonstrate that ablation of the two Nat genes is associated with modest, intermittent alterations in respiratory exchange rate. Pyruvate tolerance tests show that double KO mice have attenuated hepatic gluconeogenesis when maintained on a high‐fat/high‐sucrose diet. Absence of the two Nat genes also leads to an increase in the hepatic concentration of coenzyme A in mice fed a high‐fat/high‐sucrose diet. Our results suggest a modest involvement of NAT in energy metabolism in mice, which is consistent with the absence of major phenotypic deregulation of energy metabolism in slow human acetylators.

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“…; Camporez et al . , ). Together, these studies support the paradigm that DAG accumulation in muscle can lead to muscle insulin resistance through activation of PKCθ.…”

Section: Discussionmentioning

confidence: 99%

Anti‐inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid‐induced insulin resistance

Camporez

Lyu

Goldberg

et al. 2019

The Journal of Physiology

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Key pointsr Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies.r Insulin sensitivity is greater in premenopausal women compared with age-matched men, and metabolism-related cardiovascular diseases and type 2 diabetes are less frequent in these same women.r Both female and male mice treated with oestradiol are protected against obesity-induced insulin resistance.r The protection against obesity-induced insulin resistance is associated with reduced ectopic lipid content in liver and skeletal muscle.r These results were associated with increased insulin-stimulated suppression of white adipose tissue lipolysis and reduced inflammation.Abstract Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Overall, females are protected against obesity-induced insulin resistance; yet, the mechanisms responsible for this protection are not well understood. Therefore, the aim of the present work was to evaluate the underlying mechanism(s) by which female mice are protected against obesity-induced insulin resistance compared with male mice. We studied male and female mice in age-matched or body weight-matched conditions. They were fed a high-fat diet (HFD) or regular chow for 4 weeks. We also studied HFD male mice treated with oestradiol or vehicle. Both HFD female Joao Paulo Camporez, PhD, is an Assistant Professor of Human Physiology in the Department of Physiology and Biophysics in the Institute of Biomedical Sciences at the University of Sao Paulo. He completed his graduate training at the University of Sao Paulo and was a postdoctoral fellow at Yale University School of Medicine where he joined the research faculty and served as Co-Director of the NIH-funded Yale Mouse Metabolic Phenotyping Center In Vivo Metabolism Core. His lab is primary interested in the mechanisms of lipid-induced metabolic diseases, such as non-alcoholic fatty liver disease, insulin resistance and type 2 diabetes.3886 J. P. Camporez and others J Physiol 597.15and HFD male mice treated with oestradiol displayed increased whole-body insulin sensitivity, associated with reduction in ectopic hepatic and muscle lipid content compared to HFD male mice. Reductions in ectopic lipid content in these mice were associated with increased insulin-stimulated suppression of white adipose tissue (WAT) lipolysis. Both HFD female and HFD male mice treated with oestradiol also displayed striking reductions in WAT inflammation, represented by reductions in plasma and adipose tissue tumour necrosis factor α and interleukin 6 concentrations. Taken together these data support the hypothesis that HFD female mice are protected from obesity-induced insulin resistance due to oestradiol-mediated reductions in WAT inflammation, leading to improved insulin-mediated suppression of WAT lipolysis and reduced ectopic lipid content in liver and skeletal muscle.

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Mechanism by which arylamine N -acetyltransferase 1 ablation causes insulin resistance in mice

Cited by 54 publications

References 43 publications

Loss of human arylamine N-acetyltransferase I regulates mitochondrial function by inhibition of the pyruvate dehydrogenase complex

Loss of human arylamine N-acetyltransferase I regulates mitochondrial function by inhibition of the pyruvate dehydrogenase complex

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

Anti‐inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid‐induced insulin resistance

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