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

限制卡路里的体重减轻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，多年来它产生了明显的、长期的体重减轻。已有研究表明，由于脂肪摄入量过多而导致的奖赏低敏会引起代偿性过度进食，从而加剧体重增加。像Roux-en-Y胃分流术(RYGB)这样的减肥手术后，美味、高能量食物的奖励值发生了变化，这被认为是术后低体重稳定的关键因素。然而，尽管纹状体中强健的多巴胺(DA)功能是表达正常的奖赏行为所必需的，但它仍然难以捉摸，通过肠道的营养通道的解剖改变如何改变中央食物奖赏处理，以及它在防止体重恢复中的功能作用。最近研究表明，过度放纵高脂肪(HF)食物后，肠道合成乙醇酰胺油酰乙醇胺(OEA)减少与迟钝的喂养诱导背侧纹状体DA释放有关，而OEA外源补充恢复纹状体DA水平，导致食物摄入量减少，改进的饮食享乐评估和体重减少。然而，RYGB手术对HF喂养诱导的OEA动员的影响以及它在手术相关的饮食脂肪奖励和体重变化中的作用尚不清楚。此外，将RYGB诱导的肠道营养感知重塑传递到多巴胺能奖赏系统的信号通路，导致术后改变享乐进食行为的信号通路仍然完全缺乏。我们的主要假设是，术后肠源性脂质信使动员的变化，如OEA，通过纹状体多巴胺能奖励回路的功能改变，对RYGB术后体重减轻的维持起重要作用。在拟议的项目中，为了确定RYGB后修改的肠道DA信号的潜在机制及其在改变HF食物的奖赏价值和稳定的体重减少中的作用，我们将使用RYGB手术的饮食诱导的肥胖啮齿动物模型来(I)研究手术对异常的多巴胺能纹状体功能和HF喂养诱导的肠道OEA合成的影响，(Ii)表征肠道OEA信号和背侧DA传递在术后改变的食物摄入和享乐加工中的作用，以及(Iii)明确化学修饰纹状体神经元活性对RYGB维持性体重减轻的影响。总之，我们对RYGB手术后肠道营养感知和享乐食物感知之间的变化相互作用的研究将为DIO中特定的信号通路、潜在的变化的奖赏感觉提供新的见解，并可能为未来更有效的肥胖“无刀”治疗策略确定新的靶点。

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.