A double knockout for zinc transporter 8 and somatostatin in mice reveals their distinct roles in regulation of insulin secretion and obesity.

IF 3.3 3区 医学 Q2 GENETICS & HEREDITY
Zhongyue Yang, Catherine P Kirschke, Yimeng Cai, Liping Huang
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Abstract

Background: Both zinc transporter 8 (ZnT8) and somatostatin (Sst) play crucial roles in the regulation of insulin and glucagon secretion. However, the interaction between them in controlling glucose metabolism was not well understood. The aim of this study was to explore the interactive effects of a double knockout of Znt8 and Sst on insulin and glucose metabolism in mice.

Methods: Co-expression of ZnT8 with hormones secreted from gastrointestinal endocrine cells of mice was determined using immunofluorescence. Male Znt8 knockout (Znt8KO), Sst knockout (SstKO), double knockout for Sst and Znt8 (DKO), and the wild-type (WT) mice were fed a regular chow diet (CD) or a high-fat diet (HFD) at 3 weeks old for 15 weeks. Weights and fasting or fed glucose levels were determined. Glucose and insulin tolerance tests were performed; metabolic-relevant hormone levels including insulin, glucagon, glucagon-like peptide 1, Pyy, and leptin were determined.

Results: ZnT8 is co-expressed with Sst in a subpopulation of endocrine D cells in the gastrointestinal tract. The absence of ZnT8 expression resulted in an increased density of the dense cores in the secretory granules of the D cell. DKO mice had reduced weight compared to WT when maintained on the CD. Compared to Znt8KO and SstKO, DKO mice did not show significant differences in fed or fasting blood glucose level regardless of dietary conditions. However, the CD-fed DKO mice had impaired insulin secretion without alterations in islet morphology or numbers. Moreover, DKO mice displayed diet-induced insulin resistance and disrupted secretion of metabolic-related hormones.

Conclusions: Somatostatin as well as a normal insulin sensitivity are required for normalizing glucose metabolism in Znt8KO mice. ZnT8 may play a role in regulating fat mass and leptin secretion. These findings shed light on the multifaceted nature of Znt8 and Sst interactions, opening new avenues to understand their roles in controlling glucose metabolism and fat mass.

小鼠锌转运体 8 和体生长抑素的双重基因敲除揭示了它们在调节胰岛素分泌和肥胖中的不同作用。
背景:锌转运体 8(ZnT8)和体生长抑素(Sst)在调节胰岛素和胰高血糖素分泌方面都发挥着至关重要的作用。然而,人们对它们在控制葡萄糖代谢中的相互作用还不甚了解。本研究旨在探讨 Znt8 和 Sst 双基因敲除对小鼠胰岛素和糖代谢的交互影响:方法:采用免疫荧光法测定 ZnT8 与小鼠胃肠道内分泌细胞分泌的激素的共表达。雄性 Znt8 基因敲除(Znt8KO)、Sst 基因敲除(SstKO)、Sst 和 Znt8 双基因敲除(DKO)小鼠以及野生型(WT)小鼠在 3 周大时以普通饲料(CD)或高脂饲料(HFD)喂养 15 周。测定体重和空腹或进食葡萄糖水平。进行葡萄糖和胰岛素耐量试验;测定代谢相关激素水平,包括胰岛素、胰高血糖素、胰高血糖素样肽 1、Pyy 和瘦素:结果:ZnT8 与 Sst 在胃肠道内分泌 D 细胞亚群中共同表达。ZnT8 的缺失会导致 D 细胞分泌颗粒中的致密核心密度增加。与WT相比,DKO小鼠在CD上的体重有所减轻。与 Znt8KO 和 SstKO 相比,无论饮食条件如何,DKO 小鼠的进食或空腹血糖水平都没有显著差异。然而,CD喂养的DKO小鼠胰岛素分泌受损,但胰岛形态或数量没有改变。此外,DKO 小鼠表现出饮食诱导的胰岛素抵抗和代谢相关激素分泌紊乱:结论:Znt8KO 小鼠的糖代谢正常化需要体生长抑素和正常的胰岛素敏感性。ZnT8可能在调节脂肪量和瘦素分泌方面发挥作用。这些发现揭示了Znt8和Sst相互作用的多面性,为了解它们在控制糖代谢和脂肪量方面的作用开辟了新途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Genes and Nutrition
Genes and Nutrition 生物-遗传学
CiteScore
6.60
自引率
0.00%
发文量
14
审稿时长
6-12 weeks
期刊介绍: This journal examines the relationship between genetics and nutrition, with the ultimate goal of improving human health. It publishes original research articles and review articles on preclinical research data coming largely from animal, cell culture and other experimental models as well as critical evaluations of human experimental data to help deliver products with medically proven use.
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