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

针对肠脑轴促进高脂肪饮食消费者减肥

• 批准号: 10320473
• 负责人: Dana M Small
• 金额: $ 70.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320473
• 关键词: Afferent Pathways; Amides; Behavioral; Body Weight; Body Weight decreased; Brain; Clinical; Clinical stratification; Cognitive; Consumption; Corpus striatum structure; Critical Pathways; Data; Diet; Dietary Fats; Dietary Sugars; Dietary intake; Dopamine; Dorsal; Double-Blind Method; Effectiveness; Energy Metabolism; Fat-Restricted Diet; Fatty acid glycerol esters; Fingerprint; Food; Frequencies; Goals; Gold; High Fat Diet; Human; Human body; Individual; Infusion procedures; Intake; Intervention; Laboratories; Lipids; Maintenance; Measures; Mediating; Mediation; Metabolic; Modeling; Mus; Obesity; Outcome; Overweight; Pathway interactions; Patient Self-Report; Performance; Persons; Placebos; Psychological reinforcement; Questionnaires; Randomized Controlled Trials; Recommendation; Records; Reducing diet; Sampling; Signal Transduction; Stratification; Subgroup; Supplementation; Testing; Translating; Weight; Weight Gain; Wing; Work; base; behavior measurement; biomarker identification; blood-based biomarker; clinically significant; connectome based predictive modeling; fatty acid supplementation; gut-brain axis; improved; insight; neuroimaging; neurotransmission; novel; obese person; obesity treatment; outcome prediction; placebo group; pre-clinical; precision medicine; predictive marker; preference; randomized placebo controlled trial; relating to nervous system; response; saturated fat; sex; stem; therapeutic development; treatment effect; weight loss intervention; weight loss program

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.

目前的肥胖治疗方法可以有效减轻体重，但维持体重减轻仍然是一个重大挑战（Franz 等人，2007 年；Sawamoto 等人，2017 年；Wing 和 Phelan，2005 年）。拟议的工作采用精准医学方法来治疗肥胖，并特别关注减肥维持和减肥结果生物标志物的识别。我们的总体目标是检验这样的假设：与安慰剂和不食用 HFD 的 OW/OB 个体相比，经常食用高脂肪饮食 (HFD) 的超重和肥胖 (OW/OB) 个体如果每天补充肠道脂质信使油酰乙醇酰胺 (OEA)，则能够在黄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。这一假设的基本原理源于临床前研究，该研究表明，在体重不增加的情况下，高脂饮食 (HFD) 会削弱对感知饮食脂质调节脂肪增强价值至关重要的迷走神经传入通路，从而导致对低脂食物的偏好降低，并严重减弱多巴胺 (DA) 对脂质直接输注到小鼠肠道的反应（Tellez 等人） 等，2013）。这种 DA 减弱在输注 OEA 后立即逆转，并随之转向更偏爱低脂食物。我们实验室的初步数据提供了强有力的证据，证明这些影响也适用于人类，并且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减肥有非常强的调节作用。具体而言，在完成减肥计划 4 个月后，服用补充剂的高脂肪亚组平均体重减轻了 15 磅（体重减轻约 7%），相对于低脂肪亚组的治疗效果，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，以确定膳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体重维持的能力； (2) 识别预测结果并优化分层策略的生物标志物； (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脑目标来维持减肥，并支持一种易于实施且成本低廉的行为减肥+补充剂的精准医学方法。