| Title: |
Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis |
| Authors: |
Yang, Y; van der Klaauw, AA; Zhu, L; Cacciottolo, TM; He, Y; Stadler, LKJ; Wang, C; Xu, P; Saito, K; Hinton, A; Yan, X; Keogh, JM; Henning, E; Banton, MC; Hendricks, AE; Bochukova, EG; Mistry, V; Lawler, KL; Liao, L; Xu, J; O'Rahilly, S; Tong, Q; Barroso, I; O'Malley, BW; Farooqi, IS; Xu, Y; Balasubramanian, S; Clapham, P; Coates, G; Cox, T; Daly, A; Danecek, P; Du, Y; Durbin, R; Edkins, S; Ellis, P; Flicek, P; Guo, X; Huang, L; Jackson, DK; Joyce, C; Keane, T; Kolb-Kokocinski, A; Langford, C; Li, Y; Liang, J; Lin, H; Liu, R; Maslen, J; McCarthy, S; Muddyman, D; Quail, MA; Stalker, J; Sun, J; Tian, J; Wang, G; Wang, J; Wang, Y; Wong, K; Zhang, P; Birney, E; Boustred, C; Brion, M-J; Chen, L; Clement, G; Smith, GD; Day, INM; Day-Williams, A; Down, T; Dunham, I; Evans, DM; Fatemifar, G; Gaunt, TR; Geihs, M; Greenwood, CMT; Hart, D; Howie, B; Huang, J; Hubbard, T; Hysi, P; Iotchkova, V; Jamshidi, Y; Kemp, JP; Lachance, G; Lawson, D; Lek, M; Lopes, M; MacArthur, DG; Marchini, J; Massimo, M; Mathieson, I; Memari, Y; Metrustry, S; Min, JL; Moayyeri, A; Northstone, K; Panoutsopoulou, K; Paternoster, L; Perry, JRB; Quaye, L; Richards, JB; Ring, S; Ritchie, GRS; Schiffels, S; Shihab, HA; Shin, S-Y; Small, KS; Artigas, MS; Soranzo, N; Southam, L; Spector, TD; St Pourcain, B; Surdulescu, G; Tachmazidou, I; Timpson, NJ; Tobin, MD; Valdes, AM; Visscher, PM; Wain, LV; Walter, K; Ward, K; Wilson, SG; Yang, J; Zeggini, E; Zhang, F; Zheng, H-F; Anney, R; Ayub, M; Barrett, JC; Blackwood, D; Bolton, PF; Breen, G; Collier, DA; Craddock, N; Crooks, L; Curran, S; Curtis, D; Gallagher, L; Geschwind, D; Gurling, H; Holmans, P; Lee, I; Lonnqvist, J; McGuffin, P; McIntosh, AM; McKechanie, AG; McQuillin, A; Morris, J; O'Donovan, MC; Owen, MJ; Palotie, A; Parr, JR; Paunio, T; Pietilainen, O; Rehnstrom, K; Sharp, SI; Skuse, D; St Clair, D; Suvisaari, J; Walters, JTR; Williams, HJ; Bochukova, E; Bounds, R; Dominiczak, A; Keogh, J; Marenne, G; Morris, A; Porteous, DJ; Smith, BH; Wheeler, E; Al Turki, S; Anderson, CA; Antony, D; Beales, P; Bentham, J; Bhattacharya, S; Calissano, M; Carss, K; Chatterjee, K; Cirak, S; Cosgrove, C; Fitzpatrick, DR; Floyd, J; Foley, AR; Franklin, CS; Futema, M; Grozeva, D; Humphries, SE; Hurles, ME; Mitchison, HM; Muntoni, F; Onoufriadis, A; Parker, V; Payne, F; Plagnol, V; Raymond, FL; Roberts, N; Savage, DB; Scambler, P; Schmidts, M; Schoenmakers, N; Semple, RK; Serra, E; Spasic-Boskovic, O; Stevens, E; van Kogelenberg, M; Vijayarangakannan, P; Williamson, KA; Wilson, C; Whyte, T; Ciampi, A; Li, R; Oualkacha, K; Xu, C; Bobrow, M; Griffin, H; Kaye, J; Kennedy, K; Kent, A; Smee, C; Charlton, R; Ekong, R; Khawaja, F; Lopes, LR; Migone, N; Payne, SJ; Pollitt, RC; Povey, S; Ridout, CK; Robinson, RL; Scott, RH; Shaw, A; Syrris, P; Taylor, R; Vandersteen, AM; Amuzu, A; Casas, JP; Chambers, JC; Cocca, M; Dedoussis, G; Gambaro, G; Gasparini, P; Isaacs, A; Johnson, J; Kleber, ME; Kooner, JS; Langenberg, C; Luan, J; Malerba, G; Marz, W; Matchan, A; Morris, R; Nordestgaard, BG; Benn, M; Scott, RA; Toniolo, D; Traglia, M; Tybjaerg-Hansen, A; van Duijn, CM; van Leeuwen, EM; Varbo, A; Whincup, P; Zaza, G; Zhang, W |
| Source: |
Nature Communications , 10 , Article 1718. (2019) |
| Publisher Information: |
NATURE PUBLISHING GROUP |
| Publication Year: |
2019 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; LEPTIN RESISTANCE; PROOPIOMELANOCORTIN NEURONS; SIGNAL TRANSDUCER; SOCS-3 EXPRESSION; FOOD-INTAKE; PPAR-GAMMA; ER STRESS; OBESITY; BALANCE; FOXO1 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10073734/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10073734/1/s41467-019-08737-6.pdf; https://discovery.ucl.ac.uk/id/eprint/10073734/ |
| Rights: |
open |
| Accession Number: |
edsbas.D747450A |
| Database: |
BASE |