Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption

Thomas A. Bowman; Kayleigh R. O'Keeffe; Theresa D'Aquila; Qing Wu Yan; John D. Griffin; Elizabeth A. Killion; Deanna M. Salter; Douglas G. Mashek; Kimberly K. Buhman; Andrew S. Greenberg

doi:10.1016/j.molmet.2016.01.001

Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption

Thomas A. Bowman, Kayleigh R. O'Keeffe, Theresa D'Aquila, Qing Wu Yan, John D. Griffin, Elizabeth A. Killion, Deanna M. Salter, Douglas G. Mashek, Kimberly K. Buhman, Andrew S. Greenberg

Food Science and Nutrition

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Objective: The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. Methods: To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5^-/-). Results: Ablation of ACSL5 reduced ACSL activity by ~80% in jejunal mucosa, ~50% in liver, and ~37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5^-/-, as compared to control ACSL5^loxP/loxP, mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5^-/- had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5^-/- mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (~16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (~13-fold) were increased in ACSL5^-/- as compared to ACSL5^loxP/loxP. Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5^-/- mice as compared to control mice. Conclusions: In summary, ACSL5^-/- mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.

Original language	English (US)
Pages (from-to)	210-220
Number of pages	11
Journal	Molecular Metabolism
Volume	5
Issue number	3
DOIs	https://doi.org/10.1016/j.molmet.2016.01.001
State	Published - Mar 1 2016

Bibliographical note

Funding Information:
Funding: T.A.B. received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( F32-DK-095538 ). T.D. receives support from the Purdue Research Foundation .

Funding Information:
D.G.M. receives support from the NIDDK ( DK-0903634 ) and the Minnesota Obesity Center ( DK050456 ). K.K. B. receives support from the American Diabetes Association ( 7-13-IN-05 ), the Department of Defense, United States Army Medical Research Acquisition Activity ( PC131237 ), and the Indiana Clinical and Translational Sciences Institute funded, in part by Grant Number Grant # UL1TR001108 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award . A.S.G. receives support from NIEHS ( UO1-ES-020958 , RO3-ES-0227 ), NIDDK ( R01 DK098606-02 ), NIDDK-Boston Nutrition Obesity Research Center ( P30-DK-46200 ), T32 DK062032-24 , and the U.S. Department of Agriculture, Agricultural Research Service , under agreement no. 58-1950-7-70 . Dr. Greenberg is also the recipient of the Robert C and Veronica Atkins endowed Professorship in Nutrition and Metabolism at Tufts Medical School.

Publisher Copyright:
© 2016 The Authors.

Keywords

ACSL
Acyl-CoA
Dietary fat absorption
FGF21
Intestine
Liver

UN SDGs

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Bowman, T. A., O'Keeffe, K. R., D'Aquila, T., Yan, Q. W., Griffin, J. D., Killion, E. A., Salter, D. M., Mashek, D. G., Buhman, K. K., & Greenberg, A. S. (2016). Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption. Molecular Metabolism, 5(3), 210-220. https://doi.org/10.1016/j.molmet.2016.01.001

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abstract = "Objective: The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. Methods: To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5-/-). Results: Ablation of ACSL5 reduced ACSL activity by ~80% in jejunal mucosa, ~50% in liver, and ~37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5-/-, as compared to control ACSL5loxP/loxP, mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5-/- had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5-/- mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (~16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (~13-fold) were increased in ACSL5-/- as compared to ACSL5loxP/loxP. Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5-/- mice as compared to control mice. Conclusions: In summary, ACSL5-/- mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.",

keywords = "ACSL, Acyl-CoA, Dietary fat absorption, FGF21, Intestine, Liver",

author = "Bowman, {Thomas A.} and O'Keeffe, {Kayleigh R.} and Theresa D'Aquila and Yan, {Qing Wu} and Griffin, {John D.} and Killion, {Elizabeth A.} and Salter, {Deanna M.} and Mashek, {Douglas G.} and Buhman, {Kimberly K.} and Greenberg, {Andrew S.}",

note = "Funding Information: Funding: T.A.B. received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( F32-DK-095538 ). T.D. receives support from the Purdue Research Foundation . Funding Information: D.G.M. receives support from the NIDDK ( DK-0903634 ) and the Minnesota Obesity Center ( DK050456 ). K.K. B. receives support from the American Diabetes Association ( 7-13-IN-05 ), the Department of Defense, United States Army Medical Research Acquisition Activity ( PC131237 ), and the Indiana Clinical and Translational Sciences Institute funded, in part by Grant Number Grant # UL1TR001108 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award . A.S.G. receives support from NIEHS ( UO1-ES-020958 , RO3-ES-0227 ), NIDDK ( R01 DK098606-02 ), NIDDK-Boston Nutrition Obesity Research Center ( P30-DK-46200 ), T32 DK062032-24 , and the U.S. Department of Agriculture, Agricultural Research Service , under agreement no. 58-1950-7-70 . Dr. Greenberg is also the recipient of the Robert C and Veronica Atkins endowed Professorship in Nutrition and Metabolism at Tufts Medical School. Publisher Copyright: {\textcopyright} 2016 The Authors.",

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T1 - Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption

AU - Bowman, Thomas A.

AU - O'Keeffe, Kayleigh R.

AU - D'Aquila, Theresa

AU - Yan, Qing Wu

AU - Griffin, John D.

AU - Killion, Elizabeth A.

AU - Salter, Deanna M.

AU - Mashek, Douglas G.

AU - Buhman, Kimberly K.

AU - Greenberg, Andrew S.

N1 - Funding Information: Funding: T.A.B. received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( F32-DK-095538 ). T.D. receives support from the Purdue Research Foundation . Funding Information: D.G.M. receives support from the NIDDK ( DK-0903634 ) and the Minnesota Obesity Center ( DK050456 ). K.K. B. receives support from the American Diabetes Association ( 7-13-IN-05 ), the Department of Defense, United States Army Medical Research Acquisition Activity ( PC131237 ), and the Indiana Clinical and Translational Sciences Institute funded, in part by Grant Number Grant # UL1TR001108 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award . A.S.G. receives support from NIEHS ( UO1-ES-020958 , RO3-ES-0227 ), NIDDK ( R01 DK098606-02 ), NIDDK-Boston Nutrition Obesity Research Center ( P30-DK-46200 ), T32 DK062032-24 , and the U.S. Department of Agriculture, Agricultural Research Service , under agreement no. 58-1950-7-70 . Dr. Greenberg is also the recipient of the Robert C and Veronica Atkins endowed Professorship in Nutrition and Metabolism at Tufts Medical School. Publisher Copyright: © 2016 The Authors.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Objective: The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. Methods: To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5-/-). Results: Ablation of ACSL5 reduced ACSL activity by ~80% in jejunal mucosa, ~50% in liver, and ~37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5-/-, as compared to control ACSL5loxP/loxP, mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5-/- had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5-/- mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (~16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (~13-fold) were increased in ACSL5-/- as compared to ACSL5loxP/loxP. Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5-/- mice as compared to control mice. Conclusions: In summary, ACSL5-/- mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.

AB - Objective: The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. Methods: To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5-/-). Results: Ablation of ACSL5 reduced ACSL activity by ~80% in jejunal mucosa, ~50% in liver, and ~37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5-/-, as compared to control ACSL5loxP/loxP, mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5-/- had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5-/- mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (~16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (~13-fold) were increased in ACSL5-/- as compared to ACSL5loxP/loxP. Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5-/- mice as compared to control mice. Conclusions: In summary, ACSL5-/- mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.

KW - ACSL

KW - Acyl-CoA

KW - Dietary fat absorption

KW - FGF21

KW - Intestine

KW - Liver

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Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption

Abstract

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Keywords

UN SDGs

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