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

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34 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 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.

Original languageEnglish (US)
Pages (from-to)210-220
Number of pages11
JournalMolecular Metabolism
Volume5
Issue number3
DOIs
StatePublished - 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

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