Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice.

Objective: Medium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8-12 carbon atoms, have been shown to reduce food intake in rodents and humans, but the underlying mechanisms are unknown. Unlike most other fatty acids, MCFAs are absorbed from the intestine into the portal vein and enter first the liver. We thus hypothesized that MCFAs trigger the release of hepatic factors that reduce appetite.
Methods: The liver transcriptome in mice that were orally administered MCFAs as C8:0 triacylglycerol (TG) was analyzed. Circulating growth/differentiation factor 15 (GDF15), tissue Gdf15 mRNA and food intake were investigated after acute oral gavage of MCFAs as C8:0 or C10:0 TG in mice. Effects of acute and subchronic administration of MCFAs as C8:0 TG on food intake and body weight were determined in mice lacking either the receptor for GDF15, GDNF Family Receptor Alpha Like (GFRAL), or GDF15.
Results: Hepatic and small intestinal expression of Gdf15 and circulating GDF15 increased after ingestion of MCFAs, while intake of typical dietary long-chain fatty acids (LCFAs) had no effect. Plasma GDF15 levels also increased in the portal vein with MCFA intake, indicating that in addition to the liver, the small intestine contributes to the rise in circulating GDF15. Acute oral provision of MCFAs decreased food intake over 24 h compared with a LCFA-containing bolus, and this anorectic effect required the GDF15 receptor, GFRAL. Moreover, subchronic oral administration of MCFAs reduced body weight over 7 days, an effect that was blunted in mice lacking either GDF15 or GFRAL.
Conclusions: We have identified ingestion of MCFAs as a novel nutritional approach that increases circulating GDF15 in mice and have revealed that the GDF15-GFRAL axis is required for the full anorectic effect of MCFAs.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bente Kiens reports financial support was provided by Novo Nordisk Foundation. Maximilian Kleinert reports financial support was provided by Arla Food For Health. Bente Kiens reports financial support was provided by Danish Dairy Research Foundation. Josephine Maria Kanta reports financial support was provided by Danish Cardiovascular Academy. Anne-Marie Lundsgaard reports financial support was provided by Danish Diabetes Academy. Stephanie Holm reports financial support was provided by Danish Diabetes Academy. Andreas Machel Fritzen reports financial support was provided by Danish Diabetes Academy. Andreas Machel Fritzen reports financial support was provided by Novo Nordisk Foundation. Markus Jahnert reports financial support was provided by German Ministry of Education and Research. Annette Schurmann reports financial support was provided by German Ministry of Education and Research. Markus Jahnert reports financial support was provided by The Brandenburg State. Anette Schurmann reports financial support was provided by The Brandenburg State. Maximilian Kleinert reports financial support was provided by Deutsche Forschungsgemeinschaft. Maximilian Kleinert reports financial support was provided by German Center for Diabetes Research. Maximilian Kleinert reports financial support was provided by Novo Nordisk Foundation. C.C. is co-founder of Ousia Pharma ApS, a biotech company developing therapeutics for obesity. C.C. is also on the editorial board of Molecular Metabolism.
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