Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 14, 2017; 23(34): 6231-6241
Published online Sep 14, 2017. doi: 10.3748/wjg.v23.i34.6231
Changes of Ghrelin/GOAT axis and mTOR pathway in the hypothalamus after sleeve gastrectomy in obese type-2 diabetes rats
Qiang Wang, Wei Tang, Wen-Sheng Rao, Xin Song, Cheng-Xiang Shan, Wei Zhang
Qiang Wang, Wen-Sheng Rao, Xin Song, Cheng-Xiang Shan, Wei Zhang, Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Wei Tang, Department of Surgery, University of Tokyo Hospital, Tokyo 113-8655, Japan
Author contributions: Wang Q and Rao WS contributed equally to this work and should be considered as co-first authors; Tang W, Shan CX and Zhang W designed the research; Song X performed the statistical analysis; Zhang W and Wang Q wrote this paper.
Supported by the National Natural Science Foundation of China, No. 81270969 (to Wei Zhang) and No. 81300723 (to Cheng-Xiang Shan); Shanghai Science and Technology Commission, No. 12ZR1439100 (to Wei Zhang).
Institutional review board statement: This study was reviewed and approved by the institutional board and Ethics Committee of Changzheng Hospital, Shanghai, China.
Institutional animal care and use committee statement: All procedures in this study conformed to the institutional standards of the Second Military Medical University Animal Care and Use Committee (Approval No. SCXK(H) 2013-0016).
Conflict-of-interest statement: We declare that there are no conflicts of interest related to this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Zhang Wei, Professor, Department of General Surgery, Changzheng Hospital, Second Military Medical University, No. 415, Fengyang Road, Shanghai 200003, China. zhangwei412@aliyun.com
Telephone: +86-21-81885802 Fax: +86-21-63520020
Received: March 8, 2017
Peer-review started: March 9, 2017
First decision: April 21, 2017
Revised: May 2, 2017
Accepted: June 1, 2017
Article in press: June 1, 2017
Published online: September 14, 2017
Processing time: 190 Days and 14.2 Hours
Abstract
AIM

To examine the changes of the ghrelin/ghrelin O-acyltransferase (GOAT) axis and the mammalian target of rapamycin (mTOR) pathway in the hypothalamus after sleeve gastrectomy.

METHODS

A total of 30 obese type-2 diabetes Sprague-Dawley (SD) rats, 6 wk of age, fed with high-sugar and high-fat fodder for 2 mo plus intraperitoneal injection of streptozotocin were randomly divided into three groups: non-operation group (S0 group, n = 10), sham operation group (Sh group, n = 10) and sleeve gastrectomy group (SG group, n = 10). Data of body mass, food intake, oral glucose tolerance test (OGTT), acylated ghrelin (AG) and total ghrelin (TG) were collected and measured at the first day (when the rats were 6 wk old), preoperative day 3 and postoperative week 8. The mRNA expression of preproghrelin, GOAT and neuropeptide Y (NPY), and protein expression of ghrelin, GOAT, GHSR and the mTOR pathway (p-Akt, p-mTOR and p-S6) were measured in the hypothalamus.

RESULTS

SG can significantly improve metabolic symptoms by reducing body mass and food intake. The obese rats showed lower serum TG levels and no change in AG, but the ratio of AG/TG was increased. When compared with the S0 and Sh groups, the SG group showed decreased TG (1482.03 ± 26.55, 1481.49 ± 23.30 and 1206.63 ± 52.02 ng/L, respectively, P < 0.05), but unchanged AG (153.06 ± 13.74, 155.37 ± 19.30 and 144.44 ± 16.689 ng/L, respectively, P > 0.05). As a result, the ratio of AG/TG further increased in the SG group (0.103 ± 0.009, 0.105 ± 0.013 and 0.12 ± 0.016, respectively, P < 0.05). When compared with the S0 group, SG suppressed mRNA and protein levels of preproghrelin (0.63 ± 0.12 vs 0.5 ± 0.11, P < 0.05) and GOAT (0.96 ± 0.09 vs 0.87 ± 0.08, P < 0.05), but did not change NPY mRNA expression (0.61 ± 0.04 vs 0.65 ± 0.07, P > 0.05) in the hypothalamus. The protein levels of p-Akt, p-mTOR and p-S6 were higher in the SG group, which indicated that the hypothalamic mTOR pathway was activated after SG at the postoperative week 8.

CONCLUSION

The reduction of ghrelin expression and activation of the mTOR pathway might have opposite effects on food intake, as SG improves obesity and T2DM.

Keywords: Ghrelin; Ghrelin O-acyltransferase; Type-2 Diabetes; Hypothalamus; Obesity; Sleeve gastrectomy; Mammalian target of rapamycin

Core tip: Recent studies have demonstrated a complex relationship between ghrelin, ghrelin O-acyltransferase (GOAT) and the mammalian target of rapamycin (mTOR) pathway. In our study, we examined the changes of the ghrelin/GOAT axis and the mTOR pathway in the hypothalamus after sleeve gastrectomy (SG). The mRNA and protein levels of ghrelin and GOAT decreased after SG, while NPY mRNA expression did not change. We also found that SG increased the protein levels of p-Akt, p-mTOR and p-S6. The reduction of ghrelin expression and activation of the mTOR pathway might have opposite effects on food intake. These findings might explain the weight, glucose and food intake regain after SG.