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

Abstract

ObjectiveThe 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.MethodsTo elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5−/−).ResultsAblation 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.ConclusionsIn 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.

An alternative effector gene at the type 2 diabetes-associated TCF7L2 locus?

“…Reported whole-body Acsl5 knockout mice show a consistent reduction in blood glucose levels [8,9] and improvements in insulin sensitivity [8]. In line with this, the study by Xia et al shows lower ACSL5 expression in the non-risk C allele compared with the type 2 diabetes risk-increasing T allele [6].These findings are also in agreement with previous observations in human islets, which demonstrate that the T allele confers greater enhancer activity at rs7903146 [10].…”

The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5

“…In the earlier study, the long-chain acyl-CoA synthesis rate was reduced by 60% in the knockout mice, but the absorption of dietary long-chain fatty acids remained unaffected in response to a high-fat diet [21]. In contrast, a more recent study showed that ACSL5 ablation in mice increased energy expenditure and insulin sensitivity and delayed fat absorption [22]. Further investigation is warranted to assess the effect of ACSL5 activity on insulin resistance given the observations in this current study.…”

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice

“…Protein lysates of adipose tissue were centrifuged at 12,000 rpm for 60 min to remove neutral lipid [Bowman et al, 2016]. Protein lysates of adipose tissue were centrifuged at 12,000 rpm for 60 min to remove neutral lipid [Bowman et al, 2016].…”