Neural mechanisms controlling food intake and body weight after bariatric surgery

描述（由申请人提供）：减肥手术越来越多地用于治疗肥胖症和相关的2型糖尿病，但其有益作用的机制尚不清楚。最近的临床研究表明，大的早期抑制食物摄入可能是更重要的缓解糖尿病状态比以前假设的，成对喂养非手术对照受试者的胃旁路手术患者的低水平的食物摄入改善血糖控制一样多。然而，节食通常会失败，因为饥饿感增加和新陈代谢减少--搭桥手术后可疑地缺乏反调节反应。在这里，在Roux-en-Y胃旁路手术（RYGB）的新小鼠模型中，我们专注于负责保持强烈饥饿驱动的潜在机制。在RYGB小鼠和大鼠中的初步观察表明：（a）进食过度激活外侧臂旁核中的降钙素基因相关肽表达神经元，（B）减少的食物摄入量是较小的膳食量和早期饱腹感的结果， 及（c）食物的选择逐渐由高脂肪转为低脂肪。我们假设，脑干的“厌食症通路”周围的外侧臂旁核是关键参与减少RYGB后的食物摄入量，这一神经通路的神经传导能力可以被利用，以防止和扭转肥胖，而无需手术。为此，我们将确定目标1中厌食途径的关键组成部分。我们将检验目标2中厌食途径的抑制调节RYGB后食物摄入减少和体重减轻的假设。最后，我们将在目的3中测试长期刺激厌食途径以预防或逆转高脂肪饮食诱导的肥胖症以及预防非手术动物中热量限制诱导的体重减轻后体重恢复的能力。神经元和位点特异性抑制和刺激厌食途径将通过新的药物遗传学操作实现。这些研究的结果有可能确定一些关键的神经和行为机制，使减肥手术如此有效，并将这些机制的见解转化为新的药理学和行为抗肥胖疗法。

DESCRIPTION (provided by applicant): Bariatric surgery is increasingly used for the treatment of obesity and associated type-2 diabetes, but the mechanisms for the beneficial effects are not well understood. Recent clinical studies show that the large early suppression of food intake may be more important for remission of the diabetic state than previously assumed, as pair-feeding non-surgical control subjects to the low level of food intake of gastric bypass patients improved glycemic control just as much. However, dieting typically fails because of increased hunger and reduced metabolism - counter-regulatory responses that are suspiciously absent after bypass surgery. Here, in a new mouse model for Roux-en-Y gastric bypass surgery (RYGB), we focus on the potential mechanisms responsible for keeping the strong hunger drive in check. Preliminary observations in RYGB mice and rats show that: (a) eating a meal excessively activates calcitonin-gene- related peptide-expressing neurons in the external lateral parabrachial nucleus, (b) reduced food intake is the result of smaller meal size and early satiety, and (c) food choice gradually shifts from high-fat to low-fat foods. We hypothesize that the brainstem "anorexia pathway" centered around the lateral parabrachial nucleus is critically involved in the reduced food intake after RYGB and that the anorexic power of this neural pathway can be leveraged to prevent and reverse obesity without surgery. To this end, we will identify the critical components of the anorexia pathway in Aim 1. We will test the hypothesis that inhibition of the anorexia pathway moderates the reduction in food intake and weight loss after RYGB in Aim 2. Finally, we will test the ability of chronically stimulating the anorexia pathway to prevent or reverse high-fat diet- induced obesity and to prevent weight regain after calorie restriction-induced weight loss in non- surgical animals in Aim 3. Neuron- and site-specific inhibition and stimulation of the anorexia pathway will be achieved by novel pharmacogenetic manipulations. The results of these studies have the potential to identify some critical neural and behavioral mechanisms that make bariatric surgeries so efficient and to translate these mechanistic insights into new pharmacological and behavioral anti-obesity therapies.