Although free fatty acids are typically viewed as nutrients, they can also interact with G protein–coupled receptors (GPCRs) to initiate downstream signaling pathways. Ichimura et al. used mice lacking GPR120, a receptor for unsaturated long-chain free fatty acids, to investigate the role of this GPCR in metabolism. Although body weights of wild-type mice and GPR120-deficient mice fed a normal diet were similar, when fed a high-fat diet, GPR120-deficient mice showed increased body weight compared with wild-type mice, as well as increased adipocyte size, white adipose tissue (WAT), and liver fattiness, and more severe obesity-induced insulin resistance. Gene expression analysis combined with quantitative real-time polymerase chain reaction and Western analysis revealed a decrease in insulin signaling in WAT and liver of GPR120-deficient mice fed a high-fat diet, as well as a decrease in adipocyte differentiation in WAT and an increase in lipogenesis in liver. Moreover, lipidomics analysis uncovered abnormalities in lipid composition in WAT, plasma, and liver. Analyses of lean and obese humans indicated that obesity was associated with an increase in GPR120 mRNA abundance in adipose tissue, and GPR120 exon sequencing identified a nonsynonymous p.R270H mutation associated with obesity. Stimulation of calcium signals by the GPR120 agonist α-linoleic acid (ALA) was impaired in human T-REx 293 cells expressing a transgene encoding the p.R270H receptor compared with those expressing wild-type GPR120, and coexpressing the p.R270H variant suppressed the response of the wild-type receptor. Moreover, ALA induced GLP-1 (glucagon-like peptide-1) secretion from human intestinal NCI-H716 cells expressing the wild-type receptor but not those expressing the p.R270H variant. The authors thus conclude that GPR120 dysfunction can contribute to obesity in both humans and mice.
A. Ichimura, A. Hirasawa, O. Poulain-Godefroy, A. Bonnefond, T. Hara, L. Yengo, I. Kimura, A. Leloire, N. Liu, K. Iida, H. Choquet, P. Besnard, C. Lecoeur, S. Vivequin, K. Ayukawa, M. Takeuchi, K. Ozawa, M. Tauber, C. Maffeis, A. Morandi, R. Buzzetti, P. Elliott, A. Pouta, M.-R. Jarvelin, A. Körner, W. Kiess, M. Pigeyre, R. Caiazzo, W. Van Hul, L. Van Gaal, F. Horber, B. Balkau, C. Lévy-Marchal, K. Rouskas, A. Kouvatsi, J. Hebebrand, A. Hinney, A. Scherag, F. Pattou, D. Meyre, T.-a. Koshimizu, I. Wolowczuk, G. Tsujimoto, P. Froguel, Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012). [PubMed]