Chronic suppression of acetyl-CoA carboxylase 1 in β-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism

Sarah M. Ronnebaum, Jamie W. Joseph, Olga Ilkayeva, Shawn C. Burgess, Danhong Lu, Thomas C. Becker, A. Dean Sherry, Christopher B. Newgard

Research output: Contribution to journalArticle

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Abstract

Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to β-cells suppressed [14C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.

Original languageEnglish (US)
Pages (from-to)14248-14256
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number21
DOIs
StatePublished - May 23 2008

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Acetyl-CoA Carboxylase
Lipid Metabolism
Insulin
Glucose
Cells
Pyruvic Acid
Adenosine Diphosphate
Small Interfering RNA
Adenosine Triphosphate
Substrate Cycling
Glucokinase
Citric Acid Cycle
Enzyme activity
Medical problems
Dyslipidemias
Glycogen
Islets of Langerhans
Metabolism
Adenoviridae
Insulin Resistance

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Chronic suppression of acetyl-CoA carboxylase 1 in β-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. / Ronnebaum, Sarah M.; Joseph, Jamie W.; Ilkayeva, Olga; Burgess, Shawn C.; Lu, Danhong; Becker, Thomas C.; Sherry, A. Dean; Newgard, Christopher B.

In: Journal of Biological Chemistry, Vol. 283, No. 21, 23.05.2008, p. 14248-14256.

Research output: Contribution to journalArticle

Ronnebaum, Sarah M. ; Joseph, Jamie W. ; Ilkayeva, Olga ; Burgess, Shawn C. ; Lu, Danhong ; Becker, Thomas C. ; Sherry, A. Dean ; Newgard, Christopher B. / Chronic suppression of acetyl-CoA carboxylase 1 in β-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 21. pp. 14248-14256.
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abstract = "Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80{\%} in 832/13 cells and islets and enzyme activity by 46{\%} compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70{\%} in 832/13 cells and by 33{\%} in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49{\%}, and the ATP:ADP ratio by 52{\%}, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25{\%}, which correlated with a 36{\%} decrease in glycogen synthesis and a 33{\%} decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to β-cells suppressed [14C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.",
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T1 - Chronic suppression of acetyl-CoA carboxylase 1 in β-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism

AU - Ronnebaum, Sarah M.

AU - Joseph, Jamie W.

AU - Ilkayeva, Olga

AU - Burgess, Shawn C.

AU - Lu, Danhong

AU - Becker, Thomas C.

AU - Sherry, A. Dean

AU - Newgard, Christopher B.

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N2 - Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to β-cells suppressed [14C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.

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