Objective: In the small intestine, the products of digestion of dietary triacylglycerol (TAG), fatty acids (FA) and monoacylglycerol, are taken up by absorptive cells, enterocytes, for systemic energy delivery. These digestion products can also bind receptors on endocrine cells to stimulate the release of hormones capable of influencing systemic energy metabolism. The initial phase of intestinal FA absorption involves the acylation of FAs to acyl-CoA by the acyl-CoA long chain synthetase (ACSL) enzymes. ACSL5 is abundantly expressed in the small intestinal epithelium where it is the major ACSL isoform, contributing approximately 80% of total ACSL activity. In mice with whole body de ficiency of ACSL5, the rate of dietary fat absorption is reduced and energy expenditure is increased. However, the mechanisms by which intestinal ACSL5 contributes to intestinal FA metabolism, enteroendocrine signaling, and regulation of energy expenditure remain unde fined. Here, we test the hypothesis that intestinal ACSL5 regulates energy metabolism by in fluencing dietary fat absorption and enteroendocrine signaling. Methods: To explore the role of intestinal ACSL5 in energy balance and intestinal dietary fat absorption, a novel mouse model of intestine speci fic ACSL5 de ficiency (ACSL5 IKO ) was generated by breeding ACSL5 floxed (ACSL5 loxP/loxP ) to mice harboring the tamoxifen inducible, villin-Cre recombinase. ACSL5 IKO and control, ACSL5 loxP/loxP mice were fed chow (low in fat) or a 60% high fat diet (HFD), and metabolic phenotyping was performed including, body weight, body composition, insulin and glucose tolerance tests, energy expenditure, physical activity, and food intake studies. Pair -feeding studies were performed to determine the role of food intake in regulating development of obesity. Studies of dietary fat absorption, fecal lipid excretion, intestinal mucosal FA content, and circulating levels of glucagon like peptide 1 (GLP-1) and peptide YY (PYY) in response to a TAG challenge were performed. Treatment with a GLP-1 receptor antagonist was performed to determine the contribution of GLP-1 to acute regulation of food intake. Results: We found that ACSL5 IKO mice experienced rapid and sustained protection from body weight and fat mass accumulation during HFD feeding. While intestine speci fic de ficiency of ACSL5 delayed gastric emptying and reduced dietary fat secretion, it did not result in increased excretion of dietary lipid in feces. Energy expenditure and physical activity were not increased in ACSL5 IKO mice. Mice de ficient in intestinal ACSL5 display signi ficantly reduced energy intake during HFD, but not chow feeding. When HFD intake of control mice was matched to ACSL5 IKO during pair -feeding studies, no differences in body weight or fat mass gain were observed between groups. Postprandial GLP-1 and PYY were signi ficantly elevated in ACSL5 IKO mice secondary to increased FA content in the distal small intestine. Blockade of GLP-1 signaling by administration of a long -acting GLP-1 receptor antagonist partially restored HFD intake of ACSL5 IKO . Conclusions: These data indicate that intestinal ACSL5 serves as a critical regulator of energy balance, protecting mice from diet -induced obesity exclusively by increasing satiety and reducing food intake during HFD feeding. The reduction in food intake observed in ACSL5 IKO mice is driven, in part, by increased postprandial GLP-1 and PYY secretion. These effects are only observed during HFD feeding, suggesting that altered processing of dietary fat following intestinal ACSL5 ablation contributes to GLP-1 and PYY mediated increases in satiety. (c) 2024 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
