Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food.
Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food.
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作者：
Holt MK;Richards JE;Cook DR;Brierley DI;Williams DL;Reimann F;Gribble FM;Trapp S
集中施用胰高血糖素样肽-1 (GLP-1) 可抑制食物摄入。在这里，我们证明孤束核 (NTS) 中产生 GLP-1 (PPG) 的神经元是大脑内内源性 GLP-1 的主要来源。通过白喉毒素 A 亚基 (DTA) 的病毒表达选择性消融 NTS PPG 神经元，显着降低了大脑和脊髓中活性 GLP-1 的浓度。与预期相反，这种中央 GLP-1 的损失对小鼠的随意喂养没有显着影响，既不影响每日食物摄入量，也不影响体重或葡萄糖耐量。只有在体内平衡面临更大挑战之后，PPG 神经元才成为控制食物摄入所必需的。 PPG 消融小鼠在长时间禁食和流质饮食预负荷后增加了食物摄入量。与我们的消融数据一致，表达 hM4Di 的 PPG 神经元的急性抑制并不影响随意进食，然而，它增加了禁食后重新进食的摄入量并阻止了应激引起的吞咽不足。此外，化学遗传学 PPG 神经元通过 hM3Dq 激活引起强烈的急性厌食效应。我们得出的结论是，PPG 神经元不参与初级摄入调节，但形成次级饱腹感/饱腹感回路的一部分，由心因性压力和大餐激活。鉴于其吞噬能力较低，PPG 神经元可能成为肥胖治疗中有吸引力的药物靶点。
Centrally administered glucagon-like peptide-1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A (DTA) substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake following a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding, however, it increased post-fast refeeding intake and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation, but form part of a secondary satiation/satiety circuit, activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.
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影响因子：
8.1
作者：
Holt MK;Llewellyn-Smith IJ;Reimann F;Gribble FM;Trapp S
通讯作者：
Trapp S
影响因子：
3.3
作者：
Llewellyn-Smith, I. J.;Reimann, F.;Gribble, F. M.;Trapp, S.
通讯作者：
Trapp, S.
影响因子：
3.3
作者：
Llewellyn-Smith, I. J.;Gnanamanickam, G. J. E.;Reimann, F.;Gribble, F. M.;Trapp, S.
通讯作者：
Trapp, S.
DOI：
10.1523/jneurosci.3141-10.2010
发表时间：
2010-09-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Marina N;Abdala AP;Trapp S;Li A;Nattie EE;Hewinson J;Smith JC;Paton JF;Gourine AV
通讯作者：
Gourine AV
影响因子：
3.3
作者：
Larsen, PJ;TangChristensen, M;Orskov, C
通讯作者：
Orskov, C