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

目前用于肥胖症治疗的疗法在产生体重减轻方面是有效的，但体重减轻的维持仍然是一个重大挑战（Franz等人，2007; Sawamoto等人，2017年; Wing和Dallan，2005年）。拟议的工作采用精确医学方法治疗肥胖症，并特别关注减肥维持和减肥结果生物标志物的识别。我们的首要目标是检验以下假设：与安慰剂相比以及与不食用高脂饮食（HFD）的OW/OB个体相比，如果他们每天补充肠道脂质信使油酰乙醇胺（OEA），则经常食用高脂饮食（HFD）的超重和肥胖（OW/OB）个体能够在金标准行为减肥干预后减轻更多体重并保持更大的体重减轻。该假设的基本原理源于临床前工作，其显示对于感测调节脂肪强化值的膳食脂质至关重要的迷走神经传入途径在没有体重增加的情况下被高脂肪饮食（HFD）钝化，导致对低脂食物的偏好降低和多巴胺（DA）对脂质直接输注到小鼠肠道的反应严重钝化（Tellez等人，2013年）。这种DA钝化在OEA输注后立即逆转，伴随着对低脂食物的更大偏好。我们实验室的初步数据提供了强有力的证据，证明这些影响转化为人类，在一项试点随机对照试验（RCT）中，我们发现基线自我报告的脂肪摄入量对体重减轻有非常强的调节作用。具体而言，相对于低脂肪亚组的治疗效果，补充剂的高脂肪亚组在完成减肥计划后4个月平均体重减轻15磅（体重减轻约7%），p=0.006。因此，我们的目的是（1）在OW/OB个体中进行RCT，以确定饮食脂肪摄入是否调节OEA在金标准行为减肥治疗后改善体重减轻和维持体重减轻的能力;（2）确定预测结果的生物标志物并优化分层策略;（3）测试OEA有效性的基础模型。如果成功，这项工作将确定一个新的肠道-大脑目标，以维持减肥，并支持一种精确的医学方法，以行为减肥+补充，这是容易和廉价的实施。

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.