Combination of obesity and high-fat feeding diminishes sensitivity to GLP-1R agonist exendin-4.
Combination of obesity and high-fat feeding diminishes sensitivity to GLP-1R agonist exendin-4.
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作者：
Duca FA;Sakar Y;Covasa M
在肥胖症中，抑制食欲的胃肠道机制受到损害。胰高血糖素样肽-1（GLP-1）响应营养素而释放，抑制食物摄入，并已显示在调节能量平衡中发挥作用。尚不清楚肥胖倾向（OP）大鼠是否表现出可能导致营养诱导的饱足和摄食过多减少的GLP-1信号传导功能障碍。因此，我们检查了GLP-1 R激动剂exendin-4（Ex-4）外源性腹膜内给药对OP和肥胖抵抗（OR）大鼠在饲料或高能量/高脂肪（HE/HF）喂养期间摄食量的影响。所有剂量的Ex-4均有效抑制了喂食食物的OP和OR大鼠的摄入;然而，在HE/HF喂食期间，在所有测试的Ex-4剂量下，OP大鼠抑制的摄入显著低于OR大鼠。这与OP大鼠迷走神经结状神经节中GLP-1 R mRNA表达下调有关。此外，HE/HF喂养的OP大鼠血浆GLP-1水平显著降低，肠上皮中GLP-1蛋白水平降低，回肠末端L细胞数量减少。这些结果表明，HE/HF喂养，加上OP表型，导致内源性GLP-1和GLP-1 R活化减少，表明肥胖期间GLP-1信号传导受损可能加剧摄食过多和体重增加。
Gastrointestinal mechanisms involved in the suppression of appetite are compromised in obesity. Glucagon-like peptide-1 (GLP-1) is released in response to nutrients, suppresses food intake, and has been shown to play a role in regulation of energy balance. It is not known whether obese-prone (OP) rats exhibit dysfunctional GLP-1 signaling that could contribute to decreased nutrient-induced satiation and hyperphagia. Therefore, we examined the effects of exogenous intraperitoneal administration of the GLP-1R agonist, exendin-4 (Ex-4), on food intake in OP and obese-resistant (OR) rats during chow or high-energy/high-fat (HE/HF) feeding. All doses of Ex-4 effectively suppressed intake in OP and OR rats fed chow; however, during HE/HF-feeding, OP rats suppressed intake significantly less than OR rats at all Ex-4 doses tested. This was associated with downregulation of GLP-1R mRNA expression in the vagal nodose ganglia of OP rats. Furthermore, HE/HF-fed OP rats had significantly lower plasma GLP-1 levels, decreased protein levels of GLP-1 in the intestinal epithelium, and reduced number of L cells in the distal ileum. These results demonstrate that HE/HF-feeding, coupled with OP phenotype, results in reduced endogenous GLP-1 and GLP-1R activation, indicating that impaired GLP-1 signaling during obesity may exacerbate hyperphagia and weight gain.
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影响因子：
2.9
作者：
Hayes, Matthew R.;De Jonghe, Bart C.;Kanoski, Scott E.
通讯作者：
Kanoski, Scott E.
DOI：
10.1152/ajpregu.00290.2005
发表时间：
2005-10-01
影响因子：
2.8
作者：
Little, TJ;Feltrin, KL;Feinle-Bisset, C
通讯作者：
Feinle-Bisset, C
DOI：
10.1152/ajpendo.90796.2008
发表时间：
2009-04-01
影响因子：
5.1
作者：
Paulino, Gabriel;de la Serre, Claire Barbier;Raybould, Helen E.
通讯作者：
Raybould, Helen E.
影响因子：
6.9
作者：
Reidelberger, Roger D.;Haver, Alvin C.;Steenson, Sharalyn M.
通讯作者：
Steenson, Sharalyn M.
影响因子：
5.8
作者：
Carr, Richard D.;Larsen, Marianne O.;Ahren, Bo
通讯作者：
Ahren, Bo