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

目前的肥胖治疗方法在减肥方面是有效的，但减肥维持仍然是一个重大挑战（Franz等人，2007；Sawamoto等人，2017；Wing和Phelan， 2005）。这项工作将采用精准医学方法治疗肥胖，并特别关注减肥维持和减肥结果生物标志物的鉴定。我们的首要目标是验证超重和肥胖（OW/OB）经常食用高脂肪饮食（HFD）的个体，如果他们每天补充肠道脂质信使油基乙醇酰胺（OEA），与安慰剂和不食用HFD的OW/OB个体相比，在黄金标准行为减肥干预后，能够减掉更多的体重并保持更大的体重减轻。这一假设的基本原理源于临床前研究，该研究表明，在体重没有增加的情况下，高脂肪饮食（HFD）会使迷走神经传入通路（迷走神经传入通路是调节脂肪强化值的关键因素）变钝，从而导致小鼠对低脂肪食物的偏好降低，并导致多巴胺（DA）对直接向肠道注入脂质的反应严重变钝（Tellez et al., 2013）。这种DA钝化在OEA输注后立即逆转，同时转向更偏好低脂食物。我们实验室的初步数据提供了强有力的证据，证明这些影响可以转化为人类，在一项随机对照试验（RCT）中，我们发现基线自我报告的脂肪摄入量对减肥有很强的调节作用。具体来说，与低脂组相比，服用补充剂的高脂肪组在完成减肥计划4个月后平均保持了15磅的体重减轻（约7%的体重减轻），p=0.006。因此，我们的目标是：(1)在OW/OB个体中进行一项随机对照试验，以确定饮食脂肪摄入是否会调节OEA在黄金标准行为减肥治疗后改善体重减轻和维持体重的能力；(2)识别预测预后的生物标志物并优化分层策略；(3)检验oea有效性的模型。如果成功，这项工作将确定一种新的维持减肥的肠道-大脑靶点，并支持一种精确的医学方法，即行为减肥+补充，这是一种简单而廉价的实施方法。

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.