Modification of the gut-brain dopamine axis as a cause of altered food reward processing and weight loss maintenance after Roux-en-Y gastric bypass surgery in a rodent model

在啮齿动物模型中，肠脑多巴胺轴的改变是Roux-en-Y胃绕道手术后食物奖励处理和体重减轻维持改变的原因

• 批准号: 271722282
• 负责人: Professorin Dr. Wiebke Kristin Fenske
• 金额: --
• 依托单位: Rudolf-Boehm-Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/271722282?language=en
• 关键词: Modification; gut; brain; dopamine; axis

Obesity relapse following calorie-restrictive weight loss is a major problem in the management of the growing obesity threat. Bariatric surgery differs from non-invasive weight loss strategies in that it produces a pronounced and longterm bodyweight (BW) reduction over years. It has been proposed that reward hyposensitivity as a consequence of excessive fat intake exacerbates weight (re)gain by provoking compensatory overfeeding. A changed reward value of palatable, energy-dense foods after bariatric surgery like Roux-en-Y gastric bypass (RYGB) is thought to critically contribute to postoperative stabilization of lower BW. However, while robust dopamine (DA) function in the striatum is known to be required for the expression of normal reward-seeking behaviors, it still remains elusive how anatomical rerouting of nutrient passage through the gut modifies central food reward processing and what is its functional role in the prevention of weight regain.Reduced intestinal synthesis of the ethanolamide oleoylethanolamide (OEA) following overindulgence of high-fat (HF) foods has recently been shown to be associated with blunted feeding-induced DA release in the dorsal striatum, whilst exogenous replenishment with OEA restores striatal DA levels leading to reduced food intake, modified hedonic evaluation of fatty diet and BW reduction. The influence, however, of RYGB surgery on HF feeding-induced OEA mobilization and its role in the surgery-related alterations in dietary fat reward and BW are unknown. Furthermore, the signaling pathway relaying RYGB-induced remodeling of gut nutrient sensing to the dopaminergic reward system, resulting in postoperatively modified hedonic eating behavior is still completely lacking. Our main hypothesis is that postoperative changes in the mobilization of gut-derived lipid messengers like OEA importantly contribute to post-RYGB weight loss maintenance by functional modification of striatal dopaminergic reward circuits.To determine in the proposed project the underlying mechanisms of modified gut-DA signaling post RYGB and its role in the altered reward value of HF foods and stable BW reduction, diet-induced obese rodent models of RYGB surgery will be used to (i) investigate the effect of surgery on aberrant dopaminergic striatal function and HF feeding-induced gut OEA synthesis, (ii) characterize the role of gut OEA signaling and dorsostriatal DA transmission in postoperatively altered food intake and hedonic processing, and (iii) to define the influence of chemical modification of striatal neuron activity on post-RYGB maintained weight reduction. Together our study of the altered interaction among intestinal nutrient sensing and hedonic food perception post RYGB surgery will provide novel insights into the specific signaling pathway, underlying altered reward sensation in DIO and may identify new targets for more efficient "knifeless" treatment strategies for obesity in the future.

限制热量减肥后的肥胖复发是管理日益增长的肥胖威胁的一个主要问题。减肥手术与非侵入性减肥策略的不同之处在于，它多年来产生显著和长期的体重（BW）减少。有人提出，奖励低敏感性作为过度脂肪摄入的结果，加剧了体重（再）增加，挑起补偿性过度喂养。在减肥手术（如Roux-en-Y胃旁路术（RYGB））后，可口的能量密集食物的奖励价值发生变化，被认为对术后低体重的稳定有重要作用。然而，虽然纹状体中强大的多巴胺（DA）功能已知是表达正常的奖励寻求行为所必需的，目前尚不清楚营养物质通过肠道的解剖学改变如何改变中枢食物奖赏处理，以及它在预防体重反弹中的功能作用。最近的研究表明，食物中的OEA与背侧纹状体中的钝性喂养诱导的DA释放有关，而OEA的外源性补充恢复了纹状体DA水平，导致食物摄入减少，脂肪饮食的享乐评价改变和BW降低。然而，RYGB手术对HF喂养诱导的OEA动员的影响及其在饮食脂肪奖励和BW的手术相关改变中的作用尚不清楚。此外，将RYGB诱导的肠道营养感测重塑中继到多巴胺能奖励系统的信号通路，导致术后修改的享乐性进食行为仍然完全缺乏。我们的主要假设是，术后肠源性脂质信使（如OEA）的动员变化通过纹状体多巴胺能奖励回路的功能修饰对RYGB后体重减轻的维持有重要作用。为了确定拟议项目中RYGB后修饰的肠DA信号转导的潜在机制及其在HF食物改变的奖励值和稳定的体重减少中的作用，RYGB手术的饮食诱导的肥胖啮齿动物模型将用于（i）研究手术对异常多巴胺能纹状体功能和HF喂养诱导的肠OEA合成的影响，（ii）表征肠OEA信号传导和背侧纹状体DA传递在手术后改变的食物摄入和享乐加工中的作用，和（iii）确定纹状体神经元活性的化学修饰对RYGB后维持的体重减轻的影响。我们对RYGB手术后肠道营养感测和享乐食物感知之间相互作用的改变的研究将为DIO中特定的信号通路、潜在的奖励感改变提供新的见解，并可能为未来更有效的肥胖“无刀”治疗策略确定新的靶点。