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

Atsuhiko Ichimura, Akira Hirasawa, Odile Poulain-Godefroy, Amélie Bonnefond, Takafumi Hara, Loïc Yengo, Ikuo Kimura, Audrey Leloire, Ning Liu, Keiko Iida, Hélène Choquet, Philippe Besnard, Cécile Lecoeur, Sidonie Vivequin, Kumiko Ayukawa, Masato Takeuchi, Kentaro Ozawa, Maithé Tauber, Claudio Maffeis, Anita Morandi, Raffaella Buzzetti, Paul Elliott, Anneli Pouta, Marjo-Riitta Jarvelin, Antje Körner, Wieland Kiess, Marie Pigeyre, Roberto Caiazzo, Wim Van Hul, Luc Van Gaal, Fritz Horber, Beverley Balkau, Claire Lévy-Marchal, Konstantinos Rouskas, Anastasia Kouvatsi, Johannes Hebebrand, Anke Hinney, Andre Scherag, François Pattou, David Meyre, Taka-aki Koshimizu, Isabelle Wolowczuk, Gozoh Tsujimoto, Philippe Froguel, Atsuhiko Ichimura, Akira Hirasawa, Odile Poulain-Godefroy, Amélie Bonnefond, Takafumi Hara, Loïc Yengo, Ikuo Kimura, Audrey Leloire, Ning Liu, Keiko Iida, Hélène Choquet, Philippe Besnard, Cécile Lecoeur, Sidonie Vivequin, Kumiko Ayukawa, Masato Takeuchi, Kentaro Ozawa, Maithé Tauber, Claudio Maffeis, Anita Morandi, Raffaella Buzzetti, Paul Elliott, Anneli Pouta, Marjo-Riitta Jarvelin, Antje Körner, Wieland Kiess, Marie Pigeyre, Roberto Caiazzo, Wim Van Hul, Luc Van Gaal, Fritz Horber, Beverley Balkau, Claire Lévy-Marchal, Konstantinos Rouskas, Anastasia Kouvatsi, Johannes Hebebrand, Anke Hinney, Andre Scherag, François Pattou, David Meyre, Taka-aki Koshimizu, Isabelle Wolowczuk, Gozoh Tsujimoto, Philippe Froguel

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.

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