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

Authors: BOWMAN, THOMAS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; O'KEEFE, KAYLEIGH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; D'AQUILA, THERESA - Purdue University; YAN, QING-WU - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GRIFFIN, JOHN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KILLION, ELIZABETH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SALTER, DEANNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MASHEK, DOUGLAS - University Of Minnesota; BUHMAN, KIMBERLY - Purdue University; GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/3/2016
Publication Date: 1/11/2016
Citation: Bowman, T.A., O'Keefe, K.R., D'Aquila, T., Yan, Q., Griffin, J.D., Killion, E., Mashek, D.G., Buhman, K.K., Greenberg, A. 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. doi: 10.1016/j.molmet.2016.01.001.

Interpretive Summary: We have limited understanding of the activity of the protein, ACSL5, in living animals despite prior liver cell culture research that shows that ACSL5 increases the synthesis of fat, and despite our understanding that ACSL proteins are enzymes that attach fatty acids to a high energy bond with Coenzyme A in different parts of the cell. We generated mice that are unable to produce any ACSL5. These mice have decreased ACSL enzyme activity in their intestine, liver and brown fat. Mice without any ACSL5 have less fat and have decreased blood glucose and fatty acids, which may explain why they are also more responsive to insulin. Mice without any ACSL5 also expend more energy without any increase in food consumption, which is likely because they have an increase in the energy hormone, FGF21 in the blood; and because they have more energy releasing proteins generated in fat tissues. Importantly, they absorb fat from the intestine more slowly after swallowing olive oil. These studies suggest that the protein ACSL5 controls whole-body energy metabolism. Thus, reducing ACSL5 may be a good treatment for obesity and insulin resistance.

Technical 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 ACLS5 in triacylglyceride (TAG) 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 approximately 80% in jejunal mucosa, approximately 50% in liver, and approximately 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 (approximately16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (approximately 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 (Pgc1a) transcript levels were increased in gonadal adipose tissue. To further evaluate intestinal function, mice were gavaged with an olive oil bolus; and the rate of TAG appearance in serum was found to be delayed in ACSL5-/- mice as compared to control mice. Conclusion: 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.