Targeting the gut-brain axis to facilitate weight loss in high fat diet consumers

目前的肥胖治疗方法在产生减肥效果方面是有效的，但保持减肥仍然是一个重大挑战(Franz等人，2007；Sawamoto等人，2017；Wing and Phelan，2005)。这项拟议的工作采用了一种精确的医学方法来治疗肥胖症，并特别关注减肥的维持和确定减肥结果的生物标记物。我们的首要目标是检验这样一个假设，即经常食用高脂饮食(HFD)的超重和肥胖(OW/OB)患者，如果与安慰剂和不摄入HFD的OW/OB患者相比，每天补充肠道脂质信使油酰乙醇胺(OEA)，他们能够在黄金标准行为减肥干预后减掉更多体重并保持更大的减肥效果。这一假说的基本原理源于临床前的研究，该研究表明，在没有体重增加的情况下，高脂饮食(HFD)会钝化迷走神经传入通路，而迷走神经传入通路对于感知膳食脂肪调节脂肪的强化价值至关重要，从而降低了对低脂食物的偏好，并严重钝化了对直接向小鼠肠道注入脂类的多巴胺(DA)反应(Tellez等人，2013年)。注射OEA后，这种DA钝化立即逆转，同时转向对低脂食物的更大偏好。来自我们实验室的初步数据提供了强有力的证据表明，这些影响转化为人类，在试点随机对照试验(RCT)中，我们发现基线自我报告的脂肪摄入量对体重减轻具有非常强的调节作用。具体地说，服用补充剂的高脂肪亚组在完成减肥计划4个月后，相对于低脂肪亚组的治疗效果，平均保持15磅的体重减轻(~7%的体重减轻)，p=0.006。因此，我们的目标是(1)在OW/OB个体中进行随机对照试验，以确定饮食脂肪摄入量是否影响OEA改善减肥和在黄金标准行为减肥治疗后保持减肥的能力；(2)确定预测结果的生物标志物并优化分层策略；以及(3)测试OEA有效性的模型。如果成功，这项工作将确定一种新的肠道-大脑减肥维持目标，并支持一种易于实施且成本低廉的行为减肥+补充的精确医学方法。

Current therapies for obesity treatment are effective at producing weight loss but weight loss maintenance remains a significant challenge (Franz et al., 2007; Sawamoto et al., 2017; Wing and Phelan, 2005). The proposed work takes a precision medicine approach to obesity treatment and focuses specifically on weight loss maintenance and identification of biomarkers for weight loss outcomes. Our overarching goal is to test the hypothesis that individuals with overweight and obesity (OW/OB) who regularly consume a high fat diet (HFD) are able to lose more weight and maintain greater weight loss following a gold standard behavioral weight loss intervention if they supplement daily with the gut lipid messenger oleoylthanolamide (OEA) compared to a placebo and compared to OW/OB individuals who do not consume a HFD. The rationale for this hypothesis stems from preclinical work showing that a vagal afferent pathway critical for sensing dietary lipids regulating the reinforcing value of fat is blunted by a high fat diet (HFD) in the absence of weight gain, resulting in reduced preference for low fat foods and severe blunting of dopamine (DA) response to the infusion of lipids directly to the gut of mice (Tellez et al., 2013). This DA blunting is immediately reversed upon OEA infusion with concomitant shifts to greater preferences of low-fat food. Preliminary data from our laboratory provide strong evidence that these effects translate to humans and in a pilot randomized control trial (RCT) we found a very strong modulatory effect of baseline self-reported fat intake on weight loss. Specifically, the high fat subgroup on the supplement maintained a 15 lbs weight loss on average (~7% body weight-loss) 4 months after completing a weight loss program, relative to the effect of treatment in the low-fat subgroup, p=0.006. Our aims are therefore to (1) conduct an RCT in OW/OB individuals to determine if dietary fat intake moderates the ability of OEA to improve weight loss and weight loss maintenance after a gold standard behavioral weight-loss treatment; (2) identify biomarkers that predict outcome and optimize a stratification strategy; and (3) test a model underlying OEAs effectiveness. If successful, this work will identify a novel gut-brain target for weight- loss maintenance and support a precision medicine approach to behavioral weight-loss + supplementation that is easy and inexpensive to implement.