title: FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver.
abstract: 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."
authors.affiliation: Section for Metabolic Imaging and Liver Metabolism, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Stephanie
authors.initials: S
authors.lastname: von Holstein-Rathlou
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Lucas D
authors.initials: LD
authors.lastname: BonDurant
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Lila
authors.initials: L
authors.lastname: Peltekian
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Naber
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Terry C
authors.initials: TC
authors.lastname: Yin
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Claflin
authors.affiliation: Section for Metabolic Imaging and Liver Metabolism, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Adriana Ibarra
authors.initials: AI
authors.lastname: Urizar
authors.affiliation: Section for Metabolic Receptology and Enteroendocrinology, the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Madsen
authors.affiliation: Section for Metabolic Receptology and Enteroendocrinology, the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ratner
authors.affiliation: Section for Metabolic Receptology and Enteroendocrinology, the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Karstoft
authors.affiliation: Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Vandenbeuch
authors.affiliation: Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Anderson
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Cassell
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Thompson
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; School of Sport, Exercise, and Rehabilitation Sciences, and Institute of Metabolism and Systems Research, University of Birmingham, UK.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Solomon
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Sue C
authors.initials: SC
authors.lastname: Kinnamon
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.affiliation: Section for Metabolic Imaging and Liver Metabolism, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: gillum@sund.ku.dk.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Gillum
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: matthew-potthoff@uiowa.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Potthoff
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004703:Endocrine System / Q000187:drug effects / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005518:Food Preferences / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013395:Sucrose / Q000494:pharmacology*; D013649:Taste / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D013395:Sucrose; D005346:Fibroblast Growth Factors