Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity

Yosra Alhindi (Corresponding Author), Lobke M. Vaanholt, Mustafah Al-Tarrah, Stuart R. Gray, John R. Speakman, Catherine Hambly, Bader S. Alanazi, Brendan M. Gabriel, Arimantas Lionikas, Aivaras Ratkevicius

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Abstract

Citrate synthase (CS) is a key mitochondrial enzyme. The aim of this study was to test the hypothesis that low CS activity impairs the metabolic health of mice fed a high fat diet (HFD) and promotes palmitate-induced lipotoxicity in muscle cells. C57BL/6J (B6) mice and congenic B6.A-(rs3676616-D10Utsw1)/KjnB6 (B6.A), a strain which carries the A/J allele of CS on the B6 strain background, were fed HFD (45% kcal from fat) for 12 weeks. C2C12 mouse muscle cells were used to investigate effects of CS knockdown on cell viability and signalling after incubation in 0.8 mM palmitate. CS activity, but not that of β-hydroxyacyl-coenzyme-A dehydrogenase was lower in the gastrocnemius muscle and heart of B6.A mice compared to B6 mice (P<0.001). During HFD feeding, glucose tolerance of mice decreased progressively and to a greater extent in B6.A females compared to B6 females, with males showing a similar trend. Body weight and fat gain did not differ between B6.A and B6 mice. After an 18 h incubation in 0.8 mM palmitate C2C12 muscle cells with ∼50% shRNA mediated reduction in CS activity showed lower (P<0.001) viability and increased (P<0.001) levels of cleaved caspase-3 compared to the scramble shRNA treated C2C12 cells. A/J strain variant of CS is associated with low enzyme activity and impaired metabolic health. This could be due to impaired lipid metabolism in muscle cells.

Original languageEnglish
Article number8594825
Number of pages14
JournalJournal of Nutrition and Metabolism
Volume2019
DOIs
Publication statusPublished - 3 Mar 2019

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Citrate (si)-Synthase
citrate (si)-synthase
Glucose Intolerance
glucose
mice
myocytes
Muscle Cells
Palmitates
palmitates
High Fat Diet
high fat diet
Small Interfering RNA
Congenic Mice
coenzyme A
Coenzymes
Health
caspase-3
glucose tolerance
Enzymes
lipotoxicity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Food Science
  • Nutrition and Dietetics

Cite this

Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity. / Alhindi, Yosra (Corresponding Author); Vaanholt, Lobke M.; Al-Tarrah, Mustafah; Gray, Stuart R.; Speakman, John R.; Hambly, Catherine; Alanazi, Bader S.; Gabriel, Brendan M.; Lionikas, Arimantas; Ratkevicius, Aivaras.

In: Journal of Nutrition and Metabolism, Vol. 2019, 8594825, 03.03.2019.

Research output: Contribution to journalArticle

Alhindi, Yosra ; Vaanholt, Lobke M. ; Al-Tarrah, Mustafah ; Gray, Stuart R. ; Speakman, John R. ; Hambly, Catherine ; Alanazi, Bader S. ; Gabriel, Brendan M. ; Lionikas, Arimantas ; Ratkevicius, Aivaras. / Low Citrate Synthase Activity Is Associated with Glucose Intolerance and Lipotoxicity. In: Journal of Nutrition and Metabolism. 2019 ; Vol. 2019.
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abstract = "Citrate synthase (CS) is a key mitochondrial enzyme. The aim of this study was to test the hypothesis that low CS activity impairs the metabolic health of mice fed a high fat diet (HFD) and promotes palmitate-induced lipotoxicity in muscle cells. C57BL/6J (B6) mice and congenic B6.A-(rs3676616-D10Utsw1)/KjnB6 (B6.A), a strain which carries the A/J allele of CS on the B6 strain background, were fed HFD (45{\%} kcal from fat) for 12 weeks. C2C12 mouse muscle cells were used to investigate effects of CS knockdown on cell viability and signalling after incubation in 0.8 mM palmitate. CS activity, but not that of β-hydroxyacyl-coenzyme-A dehydrogenase was lower in the gastrocnemius muscle and heart of B6.A mice compared to B6 mice (P<0.001). During HFD feeding, glucose tolerance of mice decreased progressively and to a greater extent in B6.A females compared to B6 females, with males showing a similar trend. Body weight and fat gain did not differ between B6.A and B6 mice. After an 18 h incubation in 0.8 mM palmitate C2C12 muscle cells with ∼50{\%} shRNA mediated reduction in CS activity showed lower (P<0.001) viability and increased (P<0.001) levels of cleaved caspase-3 compared to the scramble shRNA treated C2C12 cells. A/J strain variant of CS is associated with low enzyme activity and impaired metabolic health. This could be due to impaired lipid metabolism in muscle cells.",
author = "Yosra Alhindi and Vaanholt, {Lobke M.} and Mustafah Al-Tarrah and Gray, {Stuart R.} and Speakman, {John R.} and Catherine Hambly and Alanazi, {Bader S.} and Gabriel, {Brendan M.} and Arimantas Lionikas and Aivaras Ratkevicius",
note = "This work was supported by Saudi Ministry of Higher Education Grant (to Y.A.), NHS Grampian Endowment Grant (no. 12/21) (to A.R. and S.R.G.), Kuwait Ministry of Health grant (to M.A.T.), and European Social Fund under the Global Grant Measure (VP1-3.1-ŠMM-07-K-02-057) (to A.L. and A.R.). The authors thank Shona Fleming of the School of Biological Sciences, University of Aberdeen, for the technical assistance during their study. The data used to support the findings of this study are available from the corresponding author upon request. A corrigendum for this article has been published.",
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AU - Al-Tarrah, Mustafah

AU - Gray, Stuart R.

AU - Speakman, John R.

AU - Hambly, Catherine

AU - Alanazi, Bader S.

AU - Gabriel, Brendan M.

AU - Lionikas, Arimantas

AU - Ratkevicius, Aivaras

N1 - This work was supported by Saudi Ministry of Higher Education Grant (to Y.A.), NHS Grampian Endowment Grant (no. 12/21) (to A.R. and S.R.G.), Kuwait Ministry of Health grant (to M.A.T.), and European Social Fund under the Global Grant Measure (VP1-3.1-ŠMM-07-K-02-057) (to A.L. and A.R.). The authors thank Shona Fleming of the School of Biological Sciences, University of Aberdeen, for the technical assistance during their study. The data used to support the findings of this study are available from the corresponding author upon request. A corrigendum for this article has been published.

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N2 - Citrate synthase (CS) is a key mitochondrial enzyme. The aim of this study was to test the hypothesis that low CS activity impairs the metabolic health of mice fed a high fat diet (HFD) and promotes palmitate-induced lipotoxicity in muscle cells. C57BL/6J (B6) mice and congenic B6.A-(rs3676616-D10Utsw1)/KjnB6 (B6.A), a strain which carries the A/J allele of CS on the B6 strain background, were fed HFD (45% kcal from fat) for 12 weeks. C2C12 mouse muscle cells were used to investigate effects of CS knockdown on cell viability and signalling after incubation in 0.8 mM palmitate. CS activity, but not that of β-hydroxyacyl-coenzyme-A dehydrogenase was lower in the gastrocnemius muscle and heart of B6.A mice compared to B6 mice (P<0.001). During HFD feeding, glucose tolerance of mice decreased progressively and to a greater extent in B6.A females compared to B6 females, with males showing a similar trend. Body weight and fat gain did not differ between B6.A and B6 mice. After an 18 h incubation in 0.8 mM palmitate C2C12 muscle cells with ∼50% shRNA mediated reduction in CS activity showed lower (P<0.001) viability and increased (P<0.001) levels of cleaved caspase-3 compared to the scramble shRNA treated C2C12 cells. A/J strain variant of CS is associated with low enzyme activity and impaired metabolic health. This could be due to impaired lipid metabolism in muscle cells.

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