Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.

TitleDysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.
Publication TypeJournal Article
Year of Publication2012
AuthorsIchimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K, Choquet H, Besnard P, Lecoeur C, Vivequin S, Ayukawa K, Takeuchi M, Ozawa K, Tauber M, Maffeis C, Morandi A, Buzzetti R, Elliott P, Pouta A, Jarvelin M-R, Körner A, Kiess W, Pigeyre M, Caiazzo R, Van Hul W, Van Gaal L, Horber F, Balkau B, Lévy-Marchal C, Rouskas K, Kouvatsi A, Hebebrand J, Hinney A, Scherag A, Pattou F, Meyre D, Koshimizu T-aki, Wolowczuk I, Tsujimoto G, Froguel P
JournalNature
Volume483
Issue7389
Pagination350-4
Date Published2012 Mar 15
ISSN1476-4687
KeywordsAdipocytes, Adipogenesis, Adipose Tissue, Animals, Calcium Signaling, Cell Differentiation, Diet, High-Fat, DNA Mutational Analysis, Energy Metabolism, Europe, European Continental Ancestry Group, Exons, Fatty Liver, Gene Expression Regulation, Glucagon-Like Peptide 1, Glucose, Glucose Intolerance, Humans, Insulin, Insulin Resistance, Lipogenesis, Liver, Macrophages, Mice, Mutation, Obesity, Receptors, G-Protein-Coupled, Signal Transduction
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.

DOI10.1038/nature10798
Alternate JournalNature
PubMed ID22343897