TY - JOUR

T1 - Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice

AU - Kanta, Josephine Maria

AU - Deisen, Luisa

AU - Johann, Kornelia

AU - Holm, Stephanie

AU - Lundsgaard, Annemarie

AU - Lund, Jens

AU - Jähnert, Markus

AU - Schürmann, Annette

AU - Clemmensen, Christoffer

AU - Kiens, Bente

AU - Fritzen, Andreas Mæchel

AU - Kleinert, Maximilian

N1 - Copyright © 2023. Published by Elsevier GmbH.

PY - 2023

Y1 - 2023

N2 - Objective: Medium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8 to 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 MCFAs ingestion, 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 hours 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.

AB - Objective: Medium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8 to 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 MCFAs ingestion, 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 hours 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.

KW - Faculty of Science

KW - Medium-chain fatty acids

KW - Growth/differentiation factor 15

KW - Satiety

KW - Lipid metabolism

KW - Food intake

KW - Hepatokine

U2 - 10.1016/j.molmet.2023.101760

DO - 10.1016/j.molmet.2023.101760

M3 - Journal article

C2 - 37356805

VL - 74

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

M1 - 101760

ER -