FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver

• DOI: 10.1016/j.cmet.2015.12.003
• Publication Date: 2015-12-24T18:52:59Z
• Authors: Stephanie von Hol...; Lucas D. BonDurant; Lila Peltekian; Meghan C. Naber; Terry C. Yin; Kristin E. Claflin; Adriana Ibarra Ur...; Andreas N. Madsen; Cecilia Ratner; Birgitte Holst; Kristian Karstoft; Aurelie Vandenbeuch; Catherine B. Ande...; Martin D. Cassell; Anthony P. Thompson; Thomas P. Solomon; Kamal Rahmouni; Sue C. Kinnamon; Andrew A. Pieper; Matthew P. Gillum; Matthew J. Potthoff
• Keywords: Male; Mice, Knockout; Sucrose; Physiology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Nuclear Proteins; Endocrine System; Cell Biology; Feeding Behavior; Fibroblast Growth Factors; Food Preferences; Liver; Taste; Animals; Molecular Biology; Signal Transduction; Transcription Factors

The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of "sweets."