Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

被引：51

作者：

Yang, Yongjie ^{[1
]}

van der Klaauw, Agatha A. ^{[2
,3
]}

Zhu, Liangru ^{[1
,4
]}

Cacciottolo, Tessa M. ^{[2
,3
]}

He, Yanlin ^{[1
]}

Stadler, Lukas K. J. ^{[2
,3
]}

Wang, Chunmei ^{[1
]}

Xu, Pingwen ^{[1
]}

Saito, Kenji ^{[1
]}

Hinton, Antentor ^{[1
]}

Yan, Xiaofeng ^{[1
]}

Keogh, Julia M. ^{[2
,3
]}

Henning, Elana ^{[2
,3
]}

Banton, Matthew C. ^{[2
,3
]}

Hendricks, Audrey E. ^{[5
,6
]}

Bochukova, Elena G. ^{[2
,3
]}

Mistry, Vanisha ^{[2
,3
]}

Lawler, Katherine L. ^{[2
,3
]}

Liao, Lan ^{[7
]}

Xu, Jianming ^{[7
]}

O'Rahilly, Stephen ^{[2
,3
]}

Tong, Qingchun ^{[8
]}

Barroso, Ines ^{[2
,3
,5
]}

O'Malley, Bert W. ^{[7
]}

Farooqi, I. Sadaf ^{[2
,3
]}

Xu, Yong ^{[1
,7
]}

Balasubramanian, Senduran ^{[5
]}

Clapham, Peter ^{[5
]}

Coates, Guy ^{[5
]}

Cox, Tony ^{[5
]}

Daly, Allan ^{[5
]}

Danecek, Petr ^{[5
]}

Du, Yuanping ^{[9
]}

Durbin, Richard ^{[5
]}

Edkins, Sarah ^{[5
]}

Ellis, Peter ^{[5
]}

Flicek, Paul ^{[5
,10
]}

Guo, Xiaosen ^{[9
,11
]}

Guo, Xueqin ^{[9
]}

Huang, Liren ^{[9
]}

Jackson, David K. ^{[5
]}

Joyce, Chris ^{[5
]}

Keane, Thomas ^{[5
]}

Kolb-Kokocinski, Anja ^{[5
]}

Langford, Cordelia ^{[5
]}

Li, Yingrui ^{[9
]}

Liang, Jieqin ^{[9
]}

Lin, Hong ^{[9
]}

Liu, Ryan ^{[12
]}

Maslen, John ^{[5
]}

机构：

[1] Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, One Baylor Plaza, Houston, TX 77030 USA

[2] Univ Cambridge, Metab Res Labs, Cambridge CB2 0QQ, England

[3] Addenbrookes Hosp, NIHR Cambridge Biomed Res Ctr, Wellcome Trust MRC Inst Metab Sci, Cambridge CB2 0QQ, England

[4] Huazhong Univ Sci & Technol, Div Gastroenterol, Union Hosp, Tongji Med Coll, Wuhan 430022, Hubei, Peoples R China

[5] Wellcome Sanger Inst, Cambridge CB10 1SA, England

[6] Univ Colorado, Math & Stat Sci Dept, Denver, CO 80204 USA

[7] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[8] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA

[9] BGI Shenzhen, Shenzhen 518083, Peoples R China

[10] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[11] Univ Copenhagen, Dept Biol, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark

[12] BGI Europe, London EC2M 4YE, England

[13] Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada

[14] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3A 1A2, Canada

[15] King Abdulaziz Univ, Princess Al Jawhara Albrahim Ctr Excellence Res H, POB 80200, Jeddah 21589, Saudi Arabia

[16] Macau Univ Sci & Technol, Ave Wai Long, Taipa 999078, Macau, Peoples R China

[17] Univ Hong Kong, Dept Med, 21 Sassoon Rd, Hong Kong, Peoples R China

[18] Univ Hong Kong, State Key Lab Pharmaceut Biotechnol, 21 Sassoon Rd, Hong Kong, Peoples R China

[19] Univ Bristol, MRC Integrat Epidemiol Unit, Sch Social & Community Med, Oakfield House, Bristol BS8 2BN, Avon, England

[20] Univ Cambridge, Dept Haematol, Long Rd, Cambridge CB2 0PT, England

[21] Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus,Lambeth Palace Rd, London SE1 7EH, England

[22] Biogen Idec Inc, Computat Biol & Genom, 14 Cambridge Ctr, Cambridge, MA 02142 USA

[23] Kings Coll London, Dept Med & Mol Genet, Div Genet & Mol Med, Sch Med,Guys Hosp, London SE1 9RT, England

[24] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia

[25] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

[26] McGill Univ, Dept Oncol, Montreal, PQ H2W 1S6, Canada

[27] Adapt Biotechnol Corp, Seattle, WA 98102 USA

[28] St Georges Univ London, Human Genet Res Ctr, London SW17 0RE, England

[29] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[30] Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England

[31] Illumina Cambridge Ltd, Chesterford Res Pk, Cambridge CB10 1XL, England

[32] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[33] Univ Oxford, Dept Stat, 1 South Pk Rd, Oxford OX1 3TG, England

[34] St Thomas Fdn Trust, NIHR, Biomed Res Ctr, London SE1 9RT, England

[35] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[36] Imperial Coll London, Dept Epidemiol & Biostat, St Marys Campus,Norfolk Pl, London W2 1PG, England

[37] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Box 285,Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[38] McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3A 1B1, Canada

[39] Univ Bristol, ALSPAC, Oakfield House, Bristol BS8 2BN, Avon, England

[40] Univ Bristol, Sch Social & Community Med, Oakfield House, Bristol BS8 2BN, Avon, England

[41] Univ Leicester, Dept Hlth Sci & Genet, Leicester LE1 7RH, Leics, England

[42] Univ Bristol, Sch Oral & Dent Sci, Lower Maudlin St, Bristol BS1 2LY, Avon, England

[43] Univ Bristol, Sch Expt Psychol, 12a Priory Rd, Bristol BS8 1TU, Avon, England

[44] Glenfield Hosp, NIHR, Leicester Resp Biomed Res Unit, Leicester LE3 9QP, Leics, England

[45] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[46] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia

[47] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia

[48] St James Hosp, Trinity Ctr Hlth Sci, Dept Psychiat, Jamess St, Dublin 8, Ireland

[49] Queens Univ, Div Dev Disabil, Dept Psychiat, Kingston, ON N6C 0A7, Canada

[50] Univ Edinburgh, Ivis Psychiat, Royal Edinburgh Hosp, Edinburgh EH10 5HF, Midlothian, Scotland

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国惠康基金;

关键词：

LEPTIN RESISTANCE; PROOPIOMELANOCORTIN NEURONS; SIGNAL TRANSDUCER; SOCS-3; EXPRESSION; FOOD-INTAKE; PPAR-GAMMA; ER STRESS; OBESITY; BALANCE; FOXO1;

D O I：

10.1038/s41467-019-08737-6

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：

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.

引用

页数：14

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