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bioRxiv · 10.1101/2025.07.29.667447

Polyunsaturated fatty acids promote appetite via the microbiome-gut-brain axis

Liow, Y. J.·Eshima, S.·Talay, M.·Yeliseyev, V.·Bry, L.·Carmody, R. N.
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Abstract

Appetite is regulated by nutrient-sensing systems that integrate long-term signals from energy stores and short-term cues from dietary intake, yet this regulation is increasingly disrupted by industrialized diets. Although the physiological effects of industrialized diets are well documented, the continued rise in metabolic and eating disorders underscores a critical gap in our understanding of how these diets shape neural regulation of eating behavior. Here, we tested how distinct properties of industrialized diets alter brain neurochemistry and change appetite. We probed the properties of an industrialized diet through contrasts targeting the overall diet pattern (Western vs. control), enriched macronutrients (fat vs. sugar), and isocaloric trade-offs of macronutrient variants (saturated fatty acids vs. polyunsaturated fatty acids [PUFA]). The most salient effects emerged from the finest-grained contrast: PUFA conditioning increased appetite through a mechanism involving elevated brain 5-hydroxyindoleacetic acid (5-HIAA), a primary serotonin catabolite associated with the gut microbiome. Fecal microbiota transplants into germ-free mice confirmed that the PUFA-conditioned gut microbiota carries an appetite-enhancing signature. Together, our findings delineate a diet-microbiome-gut-brain axis through which dietary components of industrialized diets can modulate appetite and contribute to altered eating behavior. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/667447v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@650141org.highwire.dtl.DTLVardef@1358b06org.highwire.dtl.DTLVardef@3a4c0corg.highwire.dtl.DTLVardef@156e685_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryDietary polyunsaturated fatty acids enhance appetite via a gut microbiome-serotonergic pathway.

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Liow, Y. J., Eshima, S., Talay, M., Yeliseyev, V., Bry, L., Carmody, R. N.. 2025-07-29. Polyunsaturated fatty acids promote appetite via the microbiome-gut-brain axis. https://doi.org/10.1101/2025.07.29.667447

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