Regulation of Lipid Metabolism Related Gene and Protein Expression in White Adipose Tissue By Xenin

Presentation Number: SUN 609
Date of Presentation: April 2nd, 2017

Sharma Bhavya*, Pei San Lew and Tooru M Mizuno
University of Manitoba, Winnipeg, MB, Canada

Abstract

Gut hormones are involved in the regulation of energy balance. Xenin is a 25-amino acid peptide that belongs to the neurotensin family. It is produced by a subset of intestinal K-cells and is released into circulation after a meal. Central administration of xenin reduces food intake in rodents. Peripheral administration of xenin increases Fos expression in the central nervous system (CNS) involving the hypothalamus and reduces food intake. Feeding-suppressing effect of xenin is mediated via neurotensin receptor 1 (Ntsr1) and deletion of Ntsr1 results in obese phenotype in mice. These findings suggest the possibility that xenin acts as an endogenous satiety factor and plays a role in the regulation of whole body metabolism by activating specific cells in the CNS. However, little is known about central effect of xenin on body weight regulation and adiposity. Therefore, we tested the hypothesis that enhanced central action of xenin leads to changes in gene and protein expression of lipid metabolism in adipose tissue towards reducing adiposity. To address this hypothesis, male obese ob/ob mice underwent cannulation into the lateral ventricle and received 2 intracerebroventricular (i.c.v.) injections of xenin (5 μg/injection) at 1000 h and 2200 h under ad libitum feeding condition. Control ob/ob mice received 2 i.c.v. injections of artificial cerebrospinal fluid as vehicle control. Body weight and food intake were measured over a 24-h period. Mice were euthanized 12 h after the second injection and their epididymal white adipose tissues (WAT) were isolated for RNA and protein analyses. I.c.v. xenin treatment significantly reduced 24-h food intake (0.32 ± 0.26 g/24 h vs. 4.25 ± 0.31 g/24 h, P < 0.05) and body weight change during a 24-h period (6.34 ± 0.56 g/24 h vs. -0.85 ± 0.36 g/24 h, P < 0.05) compared to the vehicle control. Xenin treatment significantly increased adipose triglyceride lipase (Atgl) and beta-3 adrenergic-receptor (Adrb3) mRNA levels in WAT by 52.1% and 76.8%, respectively compared to the control vehicle treatment (P < 0.05). Xenin treatment caused a significant 30.3% increase in phosphorylation of hormone sensitive lipase (HSL) at Ser660 in WAT (P < 0.05), while it significantly reduced fatty acid synthase (FASN) protein levels in WAT by 41.5% compared to the control vehicle treatment (P< 0.005). These findings are consistent with our hypothesis that enhanced central action of xenin causes alterations in lipid metabolism in adipose tissue towards reduced lipogenesis and increased lipolysis, possibly contributing to xenin-induced body weight reduction. Thus, enhancing central action of xenin and its downstream targets are potential novel targets for the treatment of obesity by reducing the amount of stored fat in adipose tissue.

 

Nothing to Disclose: SB, PSL, TMM