ACSL5 is the predominant acyl-CoA synthetase (ACSL) isoform in the small intestine, comprising 90% of total ACSL activity. ACSL’s catalyze the initial step of fatty acid (FA) metabolism to form FA-CoA, which has numerous metabolic fates within cells. In previous studies, we demonstrated that mice with global ACSL5 deficiency have reduced rates of intestinal TAG secretion in response to an olive oil gavage. Furthermore, global of ablation of ACSL5 in chow fed mice reduced adiposity, improved insulin sensitivity, and increased energy expenditure. However, the role of intestinal ACSL5 in lipid absorption and regulation of systemic energy metabolism is unknown.
ACSL5 floxed mice (ACSL5-flox) were mated with mice harboring a tamoxifen inducible villin-Cre transgene to generate mice with inducible, intestine specific deficiency of ACSL5 (ACSL5-IKO).ACSL5-flox and ACSL5-IKO mice were placed on chow or 60% high fat diet (HFD) and body composition was measured by MRI. Food intake was measured in standard cages by regular weighing. Feces for fecal fat measurement were collected using wire-bottom cages. Serum was collected from overnight fasted mice gavaged with olive oil and glucagon-like peptide 1 (GLP-1) was measured via ELISA.
ACSL5-IKO mice gain 65% less fat mass after 2wk of HFD feeding in the absence of increased fecal fat loss. 2wk cumulative energy intake was reduced by 30% in ACSL5-IKO mice. Reductions in energy intake were detectable as early as 12hr following introduction of HFD. Following an olive oil gavage, the active form of the intestinal hormone GLP-1 was increased 400% in ACSL5-IKO mice.
In summary, intestine specific ablation of ACSL5 protects against diet induced obesity (DIO) by reducing food intake in the absence of fat malabsorption. The observed reductions in food intake are associated with a significant increase in postprandial active GLP-1. Further studies are underway to elucidate the underlying mechanisms protecting ACSL5-IKO mice against DIO.