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

被引：528

作者：

Ichimura, Atsuhiko ^{[2
]}

Hirasawa, Akira ^{[2
]}

Poulain-Godefroy, Odile ^{[1
]}

Bonnefond, Amelie ^{[1
]}

Hara, Takafumi ^{[2
]}

Yengo, Loic ^{[1
]}

Kimura, Ikuo ^{[2
]}

Leloire, Audrey ^{[1
]}

Liu, Ning ^{[2
]}

Iida, Keiko ^{[2
]}

Choquet, Helene ^{[1
]}

Besnard, Philippe ^{[4
]}

Lecoeur, Cecile ^{[1
]}

Vivequin, Sidonie ^{[1
]}

Ayukawa, Kumiko ^{[2
]}

Takeuchi, Masato ^{[2
]}

Ozawa, Kentaro ^{[2
]}

Tauber, Maithe ^{[5
]}

Maffeis, Claudio ^{[6
,7
]}

Morandi, Anita ^{[1
,6
]}

Buzzetti, Raffaella ^{[8
]}

Elliott, Paul ^{[9
]}

Pouta, Anneli ^{[10
,11
]}

Jarvelin, Marjo-Riitta ^{[9
,10
,12
]}

Koerner, Antje ^{[13
]}

Kiess, Wieland ^{[13
]}

Pigeyre, Marie ^{[3
,14
]}

Caiazzo, Roberto ^{[3
,14
]}

Van Hul, Wim ^{[15
]}

Van Gaal, Luc ^{[16
]}

Horber, Fritz ^{[17
,18
]}

Balkau, Beverley ^{[19
,20
]}

Levy-Marchal, Claire ^{[21
]}

Rouskas, Konstantinos ^{[1
,22
]}

Kouvatsi, Anastasia ^{[22
]}

Hebebrand, Johannes ^{[23
]}

Hinney, Anke ^{[23
]}

Scherag, Andre ^{[24
]}

Pattou, Francois ^{[3
,14
]}

Meyre, David ^{[1
,25
]}

Koshimizu, Taka-aki ^{[26
]}

Wolowczuk, Isabelle ^{[1
]}

Tsujimoto, Gozoh ^{[2
]}

Froguel, Philippe ^{[1
,27
]}

机构：

[1] Lille Pasteur Inst, CNRS, UMR 8199, F-59000 Lille, France

[2] Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Genom Drug Discovery Sci, Sakyo Ku, Kyoto 6068501, Japan

[3] Lille Nord France Univ, INSERM, U859, F-59000 Lille, France

[4] Univ Bourgogne, INSERM, UMR U866, AgroSup Dijon, F-21078 Dijon, France

[5] Ctr Hosp Univ, Childrens Hosp, INSERM, U563, F-31000 Toulouse, France

[6] Reg Ctr Juvenile Diabet Obes & Clin Nutr, I-37134 Verona, Italy

[7] Univ Verona, Dept Mother & Child, Paediat Sect, I-37134 Verona, Italy

[8] Univ Roma La Sapienza, Dept Clin Sci, I-00161 Rome, Italy

[9] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, HPA Ctr Environm & Hlth,MRC, London W2 1PG, England

[10] Univ Oulu, Natl Publ Hlth Inst, Bioctr Oulu, SF-90220 Oulu, Finland

[11] Univ Oulu, Inst Clin Med Obstet & Gynecol, SF-90220 Oulu, Finland

[12] Univ Oulu, Inst Hlth Sci, SF-90220 Oulu, Finland

[13] Univ Leipzig, Ctr Pediat Res, Dept Womens & Child Hlth, D-04317 Leipzig, Germany

[14] Lille Univ Hosp, F-59000 Lille, France

[15] Univ Antwerp, Dept Med Genet, B-2610 Antwerp, Belgium

[16] Univ Antwerp Hosp, Dept Endocrinol, B-2650 Antwerp, Belgium

[17] Clin Lindberg, Dept Med, Dept Surg & Internal Med, CH-8400 Winterthur, Switzerland

[18] Univ Bern, CH-3011 Bern, Switzerland

[19] Ctr Res Epidemiol & Populat Hlth CRESP, INSERM, U780, F-94800 Villejuif, France

[20] Univ Paris 11, F-91405 Orsay, France

[21] Hop Robert Debre, INSERM, U690, F-75935 Paris, France

[22] Aristotle Univ Thessaloniki, Sch Biol, Dept Genet Dev & Mol Biol, Thessaloniki 54124, Greece

[23] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, D-45147 Essen, Germany

[24] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, D-45122 Essen, Germany

[25] McMaster Univ, Hamilton, ON L8S 4L8, Canada

[26] Jichi Med Univ, Div Mol Pharmacol, Dept Pharmacol, Shimotsuke, Tochigi 3290498, Japan

[27] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England

来源：

NATURE | 2012年 / 483卷 / 7389期

基金：

日本科学技术振兴机构; 芬兰科学院; 日本学术振兴会; 英国医学研究理事会;

关键词：

PANCREATIC BETA-CELLS; CHAIN FATTY-ACIDS; INSULIN-RESISTANCE; BODY-MASS; CHILDHOOD OBESITY; PROTEIN FUNCTION; EARLY-ONSET; RECEPTOR; POPULATION; MUTATIONS;

D O I：

10.1038/nature10798

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes(1-4). Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases(3,5-13). 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(5,6,14-16). 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.

引用

页码：350 / U149

页数：8

共 48 条

[1] An Autocrine Lactate Loop Mediates Insulin-Dependent Inhibition of Lipolysis through GPR81 [J].