title: Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.
abstract: Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.
authors.affiliation: Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ichimura
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Odile
authors.initials: O
authors.lastname: Poulain-Godefroy
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hara
authors.forename: Loïc
authors.initials: L
authors.lastname: Yengo
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kimura
authors.forename: Audrey
authors.initials: A
authors.lastname: Leloire
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Keiko
authors.initials: K
authors.lastname: Iida
authors.forename: Hélène
authors.initials: H
authors.lastname: Choquet
authors.forename: Philippe
authors.initials: P
authors.lastname: Besnard
authors.forename: Cécile
authors.initials: C
authors.lastname: Lecoeur
authors.forename: Sidonie
authors.initials: S
authors.lastname: Vivequin
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ayukawa
authors.forename: Masato
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ozawa
authors.forename: Maithé
authors.initials: M
authors.lastname: Tauber
authors.forename: Claudio
authors.initials: C
authors.lastname: Maffeis
authors.forename: Anita
authors.initials: A
authors.lastname: Morandi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Buzzetti
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.forename: Marie
authors.initials: M
authors.lastname: Pigeyre
authors.forename: Roberto
authors.initials: R
authors.lastname: Caiazzo
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.forename: Luc
authors.initials: L
authors.lastname: Van Gaal
authors.forename: Fritz
authors.initials: F
authors.lastname: Horber
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Claire
authors.initials: C
authors.lastname: Lévy-Marchal
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Rouskas
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kouvatsi
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Andre
authors.initials: A
authors.lastname: Scherag
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Koshimizu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Wolowczuk
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D020013:Calcium Signaling; D002454:Cell Differentiation; D004252:DNA Mutational Analysis; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005060:Europe / Q000208:ethnology; D005091:Exons / Q000235:genetics; D005234:Fatty Liver / Q000150:complications / Q000235:genetics; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000150:complications; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C519853:FFAR4 protein, human; C498007:FFAR4 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D005947:Glucose