Dietary adaptation for weight loss maintenance at Yale (DAWLY): Protocol and predictions for a randomized controlled trial

Xi Fang, Xue Davis, Kyle D Flack, Chavonn Duncan, Fangyong Li, Marney White, Carlos Grilo, Dana M Small, Xi Fang, Xue Davis, Kyle D Flack, Chavonn Duncan, Fangyong Li, Marney White, Carlos Grilo, Dana M Small

Abstract

Background: Current therapies for obesity treatment are effective at producing short-term weight loss, but weight loss maintenance remains a significant challenge. Here we investigate the impact of pre-intervention dietary fat intake on the efficacy of a dietary supplement to support weight loss maintenance. Preclinical work demonstrates that a vagal afferent pathway critical for sensing dietary lipids is blunted by a high-fat diet (HFD), resulting in a reduced preference for a low-fat emulsion and severe blunting of the dopamine (DA) response to the gastric infusion of lipids. Infusion of the gut lipid messenger oleoylethanolamide (OEA), which is also depleted by HFD, immediately reverses this DA blunting and restores preference for the low-fat emulsion. Studies of OEA supplementation for weight loss in humans have had limited success. Given the strong effect of HFD on this pathway, we designed a study to test whether the efficacy of OEA as a weight loss treatment is related to pre-intervention habitual intake of dietary fat.

Methods/design: We employed a randomized, double-blind, placebo-controlled trial in which 100 adults with overweight/obesity (OW/OB) were randomized to receive either OEA or placebo daily for 16 months. Following a baseline evaluation of diet, metabolic health, adiposity, and brain response to a palatable an energy dense food, participants in both groups underwent a 4-month behavioral weight loss intervention (LEARN®) followed by a 1-year maintenance period. The study aims are to (1) determine if pre-intervention 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 OEA's effectiveness.

Discussion: Focusing on interventions that target the gut-brain axis is supported by mounting evidence for the role of gut-brain signaling in food choice and the modulation of this circuit by diet. If successful, this work will provide support for targeting the gut-brain pathway for weight loss maintenance using a precision medicine approach that is easy and inexpensive to implement.

Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT04614233].

Keywords: Riduzone; dietary intake; obesity; oleoylethanolamide; overweight; randomized controlled trial; supplementation; weight loss.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Fang, Davis, Flack, Duncan, Li, White, Grilo and Small.

Figures

FIGURE 1
FIGURE 1
Model of OEA efficacy. The relationship between diet and gut-brain signaling is shown in the context of a low-fat diet (LFD, gray box with lettuce) and a high-fat diet (HFD, red box with hamburger). Following habitual consumption HFD the vagal afferent pathway that ascends from intestine to the brain is blunted (dotted line) and this is associated with a blunted dopamine (DA) response to nutrients (red line on graph) compared to DA response to nutrients in LFD consumers (black line on graph). DA responses are associated with fat concentration preference, depicted in the preference scale above the graph. Preferences are shifted to the right in the context of a HFD. Supplementation with OEA in the HFD consumers is shown in cyan. Supplementation rescues the blunted vagal afferent pathway leading to a recovered DA response to nutrients (cyan line in graph) and a shift in preference toward low fat food. HFD, high-fat diet; LFD, low-fat diet; DA, dopamine; OEA, oleoylethanolamide. Figure created in Biorender.
FIGURE 2
FIGURE 2
Study design. OEA, oleoylethanolamide; FA, full assessment; SA, short assessment.
FIGURE 3
FIGURE 3
fMRI solution presentation. The solution run is 16-min long and consisted of a 1–10 s visual cue (average 3 s), a 1.5 s delivery of either chocolate/strawberry milkshake or tasteless solution, followed by a 6–14 s rest period (average 8 s) during which the subject could swallow. If milkshake is delivered, a 1.5 s rinse of deionized water then occurred and was followed by a 4–12 s rest period (average 6 s). There are 30 repetitions of milkshake and 30 repetitions of tasteless run. MS, milkshake; TLS, tasteless.

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