TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice.
TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice.
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DOI：
10.1136/gutjnl-2015-309871
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发表时间：
2017-03
期刊：
影响因子：
24.5
通讯作者：
Cummings BP
中科院分区：
文献类型：
--
作者：
McGavigan AK;Garibay D;Henseler ZM;Chen J;Bettaieb A;Haj FG;Ley RE;Chouinard ML;Cummings BP
垂直袖状胃切除术(VSG)可产生较高的2型糖尿病缓解率；然而，其机制仍不完全清楚。VSG可增加循环胆汁酸浓度，通过TGR5传递的胆汁酸信号可改善血糖稳态。因此，我们研究了TGR5信号在调节VSG的血糖调节益处中的作用。对高脂喂养的雄性TGR5+/+(野生型)和TGR5−/−(基因敲除)仔鼠进行血管紧张素转换酶或假手术。假手术组的小鼠被随意喂养或限制饮食，以使其体重与VSG操作的小鼠相匹配。测量体重、食物摄入量、能量消耗、胰岛素信号和循环胆汁酸谱，并进行口服葡萄糖耐量试验、胰岛免疫组织化学和肠道微生物图谱。VSG减少了食物摄入量和体重，增加了能量消耗和循环胆汁酸浓度，改善了空腹血糖、葡萄糖耐量和葡萄糖刺激的胰岛素分泌，增加了营养刺激的胰高血糖素样肽1的分泌，并使两种基因型的肠道微生物种群发生了有利的变化。然而，与TGR5+/+小鼠相比，TGR5−/−组在空腹血糖、糖耐量、肝脏胰岛素信号、肝脏炎症和胰岛形态方面的非体重依赖性改善相对减弱。此外，VSG在循环胆汁酸的代谢方面产生了有利的变化，相对于TGR5+/+小鼠，TGR5TGR5−/−的循环胆汁酸谱被钝化。TGR5对肝脏Cyp8b1表达的依赖调节可能是VSG后TGR5介导的循环胆汁酸池改变的原因之一。这些结果表明，TGR5通过促进循环胆汁酸池代谢上的有利变化来促进VSG手术的血糖调节益处。
Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG. VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5−/− (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed. VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic infiammation and islet morphology after VSG were attenuated in Tgr5−/− relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5−/− relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG. These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool.
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DOI：
10.1038/oby.2009.102
发表时间：
2009-09
期刊：
Obesity (Silver Spring, Md.)
影响因子：
--
作者：
Patti ME;Houten SM;Bianco AC;Bernier R;Larsen PR;Holst JJ;Badman MK;Maratos-Flier E;Mun EC;Pihlajamaki J;Auwerx J;Goldfine AB
通讯作者：
Goldfine AB
影响因子：
8.1
作者：
Mokadem, Mohamad;Zechner, Juliet F.;Aguirre, Vincent
通讯作者：
Aguirre, Vincent
DOI：
10.1073/pnas.0504978102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Ley, RE;Bäckhed, F;Gordon, JI
通讯作者：
Gordon, JI
影响因子：
4
作者：
Cummings, Bethany P.;Bettaieb, Ahmed;Havel, Peter J.
通讯作者：
Havel, Peter J.
DOI：
10.1073/pnas.1000080107
发表时间：
2011-03-15
影响因子：
11.1
作者：
Caporaso, J. Gregory;Lauber, Christian L.;Knight, Rob
通讯作者：
Knight, Rob