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

UK10K Consortium

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number1718
Number of pages14
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 12 Apr 2019

Cite this

@article{775fb6817bad483aba721d6b6c4ccb2f,
title = "Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis",
abstract = "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.",
keywords = "LEPTIN RESISTANCE, PROOPIOMELANOCORTIN NEURONS, SIGNAL TRANSDUCER, SOCS-3 EXPRESSION, FOOD-INTAKE, PPAR-GAMMA, ER STRESS, OBESITY, BALANCE, FOXO1",
author = "{UK10K Consortium} and Yongjie Yang and {van der Klaauw}, {Agatha A.} and Liangru Zhu and Cacciottolo, {Tessa M.} and Yanlin He and Stadler, {Lukas K. J.} and Chunmei Wang and Pingwen Xu and Kenji Saito and Antentor Hinton and Xiaofeng Yan and Keogh, {Julia M.} and Elana Henning and Banton, {Matthew C.} and Hendricks, {Audrey E.} and Bochukova, {Elena G.} and Vanisha Mistry and Lawler, {Katherine L.} and Lan Liao and Jianming Xu and Stephen O'Rahilly and Qingchun Tong and Ines Barroso and O'Malley, {Bert W.} and Farooqi, {I. Sadaf} and Yong Xu and Senduran Balasubramanian and Peter Clapham and Guy Coates and Tony Cox and Allan Daly and Petr Danecek and Yuanping Du and Richard Durbin and Sarah Edkins and Peter Ellis and Paul Flicek and Xiaosen Guo and Xueqin Guo and Liren Huang and Jackson, {David K.} and Chris Joyce and Thomas Keane and Anja Kolb-Kokocinski and Cordelia Langford and Yingrui Li and Jieqin Liang and Hong Lin and Ryan Liu and John Maslen and Shane McCarthy and Dawn Muddyman and Quail, {Michael A.} and Jim Stalker and Jianping Sun and Jing Tian and Guangbiao Wang and Jun Wang and Yu Wang and Kim Wong and Pingbo Zhang and Ewan Birney and Chris Boustred and Marie-Jo Brion and Lu Chen and Gail Clement and Petr Danecek and Smith, {George Davey} and Day, {Ian N. M.} and Aaron Day-Williams and Thomas Down and Ian Dunham and Richard Durbin and Evans, {David M.} and Ghazaleh Fatemifar and Gaunt, {Tom R.} and Matthias Geihs and Greenwood, {Celia M. T.} and Deborah Hart and Bryan Howie and Jie Huang and Tim Hubbard and Pirro Hysi and Valentina Iotchkova and Yalda Jamshidi and Kemp, {John P.} and Genevieve Lachance and Daniel Lawson and Monkol Lek and Margarida Lopes and MacArthur, {Daniel G.} and Jonathan Marchini and Mangino Massimo and Iain Mathieson and Shane McCarthy and Yasin Memari and Sarah Metrustry and Min, {Josine L.} and Alireza Moayyeri and Dawn Muddyman and Kate Northstone and Kalliope Panoutsopoulou and Lavinia Paternoster and Perry, {John R. B.} and Lydia Quaye and Richards, {J. Brent} and Susan Ring and Ritchie, {Graham R. S.} and Stephan Schiffels and Shihab, {Hashem A.} and So-Youn Shin and Small, {Kerrin S.} and Artigas, {Maria Soler} and Nicole Soranzo and Lorraine Southam and Spector, {Timothy D.} and {St Pourcain}, Beate and Gabriela Surdulescu and Ioanna Tachmazidou and Timpson, {Nicholas J.} and Tobin, {Martin D.} and Valdes, {Ana M.} and Visscher, {Peter M.} and Wain, {Louise V.} and Klaudia Walter and Kirsten Ward and Wilson, {Scott G.} and Kim Wong and Jian Yang and Eleftheria Zeggini and Feng Zhang and Hou-Feng Zheng and Richard Anney and Muhammad Ayub and Barrett, {Jeffrey C.} and Douglas Blackwood and Bolton, {Patrick F.} and Gerome Breen and Collier, {David A.} and Nick Craddock and Lucy Crooks and Sarah Curran and David Curtis and Richard Durbin and Louise Gallagher and Daniel Geschwind and Hugh Gurling and Peter Holmans and Irene Lee and Jouko Lonnqvist and Shane McCarthy and Peter McGuffin and McIntosh, {Andrew M.} and McKechanie, {Andrew G.} and Andrew McQuillin and James Morris and Dawn Muddyman and O'Donovan, {Michael C.} and Owen, {Michael J.} and Aarno Palotie and Parr, {Jeremy R.} and Tiina Paunio and Olli Pietilainen and Karola Rehnstrom and Sharp, {Sally I.} and David Skuse and {St Clair}, David and Jaana Suvisaari and Walters, {James T. R.} and Williams, {Hywel J.} and Elena Bochukova and Rebecca Bounds and Anna Dominiczak and Richard Durbin and Julia Keogh and Gaelle Marenne and Shane McCarthy and Andrew Morris and Dawn Muddyman and Porteous, {David J.} and Smith, {Blair H.} and Ioanna Tachmazidou and Eleanor Wheeler and Eleftheria Zeggini and {Al Turki}, Saeed and Anderson, {Carl A.} and Dinu Antony and Phil Beales and Jamie Bentham and Shoumo Bhattacharya and Mattia Calissano and Keren Carss and Krishna Chatterjee and Sebahattin Cirak and Catherine Cosgrove and Richard Durbin and Fitzpatrick, {David R.} and James Floyd and Foley, {A. Reghan} and Franklin, {Christopher S.} and Marta Futema and Detelina Grozeva and Humphries, {Steve E.} and Hurles, {Matthew E.} and Shane McCarthy and Mitchison, {Hannah M.} and Dawn Muddyman and Francesco Muntoni and Alexandros Onoufriadis and Victoria Parker and Felicity Payne and Vincent Plagnol and Raymond, {F. Lucy} and Nicola Roberts and Savage, {David B.} and Peter Scambler and Miriam Schmidts and Nadia Schoenmakers and Semple, {Robert K.} and Eva Serra and Olivera Spasic-Boskovic and Elizabeth Stevens and {van Kogelenberg}, Margriet and Parthiban Vijayarangakannan and Klaudia Walter and Williamson, {Kathleen A.} and Crispian Wilson and Tamieka Whyte and Antonio Ciampi and Greenwood, {Celia M. T.} and Rui Li and Sarah Metrustry and Karim Oualkacha and Ioanna Tachmazidou and ChangJiang Xu and Eleftheria Zeggini and Martin Bobrow and Bolton, {Patrick F.} and Richard Durbin and Fitzpatrick, {David R.} and Heather Griffin and Hurles, {Matthew E.} and Jane Kaye and Karen Kennedy and Alastair Kent and Dawn Muddyman and Francesco Muntoni and Fitzpatrick, {David R.} and Shane McCarthy and Richard Morris",
year = "2019",
month = "4",
day = "12",
doi = "10.1038/s41467-019-08737-6",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group - Macmillan Publishers",

}

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. / UK10K Consortium.

In: Nature Communications, Vol. 10, 1718, 12.04.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

AU - UK10K Consortium

AU - Yang, Yongjie

AU - van der Klaauw, Agatha A.

AU - Zhu, Liangru

AU - Cacciottolo, Tessa M.

AU - He, Yanlin

AU - Stadler, Lukas K. J.

AU - Wang, Chunmei

AU - Xu, Pingwen

AU - Saito, Kenji

AU - Hinton, Antentor

AU - Yan, Xiaofeng

AU - Keogh, Julia M.

AU - Henning, Elana

AU - Banton, Matthew C.

AU - Hendricks, Audrey E.

AU - Bochukova, Elena G.

AU - Mistry, Vanisha

AU - Lawler, Katherine L.

AU - Liao, Lan

AU - Xu, Jianming

AU - O'Rahilly, Stephen

AU - Tong, Qingchun

AU - Barroso, Ines

AU - O'Malley, Bert W.

AU - Farooqi, I. Sadaf

AU - Xu, Yong

AU - Balasubramanian, Senduran

AU - Clapham, Peter

AU - Coates, Guy

AU - Cox, Tony

AU - Daly, Allan

AU - Danecek, Petr

AU - Du, Yuanping

AU - Durbin, Richard

AU - Edkins, Sarah

AU - Ellis, Peter

AU - Flicek, Paul

AU - Guo, Xiaosen

AU - Guo, Xueqin

AU - Huang, Liren

AU - Jackson, David K.

AU - Joyce, Chris

AU - Keane, Thomas

AU - Kolb-Kokocinski, Anja

AU - Langford, Cordelia

AU - Li, Yingrui

AU - Liang, Jieqin

AU - Lin, Hong

AU - Liu, Ryan

AU - Maslen, John

AU - McCarthy, Shane

AU - Muddyman, Dawn

AU - Quail, Michael A.

AU - Stalker, Jim

AU - Sun, Jianping

AU - Tian, Jing

AU - Wang, Guangbiao

AU - Wang, Jun

AU - Wang, Yu

AU - Wong, Kim

AU - Zhang, Pingbo

AU - Birney, Ewan

AU - Boustred, Chris

AU - Brion, Marie-Jo

AU - Chen, Lu

AU - Clement, Gail

AU - Danecek, Petr

AU - Smith, George Davey

AU - Day, Ian N. M.

AU - Day-Williams, Aaron

AU - Down, Thomas

AU - Dunham, Ian

AU - Durbin, Richard

AU - Evans, David M.

AU - Fatemifar, Ghazaleh

AU - Gaunt, Tom R.

AU - Geihs, Matthias

AU - Greenwood, Celia M. T.

AU - Hart, Deborah

AU - Howie, Bryan

AU - Huang, Jie

AU - Hubbard, Tim

AU - Hysi, Pirro

AU - Iotchkova, Valentina

AU - Jamshidi, Yalda

AU - Kemp, John P.

AU - Lachance, Genevieve

AU - Lawson, Daniel

AU - Lek, Monkol

AU - Lopes, Margarida

AU - MacArthur, Daniel G.

AU - Marchini, Jonathan

AU - Massimo, Mangino

AU - Mathieson, Iain

AU - McCarthy, Shane

AU - Memari, Yasin

AU - Metrustry, Sarah

AU - Min, Josine L.

AU - Moayyeri, Alireza

AU - Muddyman, Dawn

AU - Northstone, Kate

AU - Panoutsopoulou, Kalliope

AU - Paternoster, Lavinia

AU - Perry, John R. B.

AU - Quaye, Lydia

AU - Richards, J. Brent

AU - Ring, Susan

AU - Ritchie, Graham R. S.

AU - Schiffels, Stephan

AU - Shihab, Hashem A.

AU - Shin, So-Youn

AU - Small, Kerrin S.

AU - Artigas, Maria Soler

AU - Soranzo, Nicole

AU - Southam, Lorraine

AU - Spector, Timothy D.

AU - St Pourcain, Beate

AU - Surdulescu, Gabriela

AU - Tachmazidou, Ioanna

AU - Timpson, Nicholas J.

AU - Tobin, Martin D.

AU - Valdes, Ana M.

AU - Visscher, Peter M.

AU - Wain, Louise V.

AU - Walter, Klaudia

AU - Ward, Kirsten

AU - Wilson, Scott G.

AU - Wong, Kim

AU - Yang, Jian

AU - Zeggini, Eleftheria

AU - Zhang, Feng

AU - Zheng, Hou-Feng

AU - Anney, Richard

AU - Ayub, Muhammad

AU - Barrett, Jeffrey C.

AU - Blackwood, Douglas

AU - Bolton, Patrick F.

AU - Breen, Gerome

AU - Collier, David A.

AU - Craddock, Nick

AU - Crooks, Lucy

AU - Curran, Sarah

AU - Curtis, David

AU - Durbin, Richard

AU - Gallagher, Louise

AU - Geschwind, Daniel

AU - Gurling, Hugh

AU - Holmans, Peter

AU - Lee, Irene

AU - Lonnqvist, Jouko

AU - McCarthy, Shane

AU - McGuffin, Peter

AU - McIntosh, Andrew M.

AU - McKechanie, Andrew G.

AU - McQuillin, Andrew

AU - Morris, James

AU - Muddyman, Dawn

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Palotie, Aarno

AU - Parr, Jeremy R.

AU - Paunio, Tiina

AU - Pietilainen, Olli

AU - Rehnstrom, Karola

AU - Sharp, Sally I.

AU - Skuse, David

AU - St Clair, David

AU - Suvisaari, Jaana

AU - Walters, James T. R.

AU - Williams, Hywel J.

AU - Bochukova, Elena

AU - Bounds, Rebecca

AU - Dominiczak, Anna

AU - Durbin, Richard

AU - Keogh, Julia

AU - Marenne, Gaelle

AU - McCarthy, Shane

AU - Morris, Andrew

AU - Muddyman, Dawn

AU - Porteous, David J.

AU - Smith, Blair H.

AU - Tachmazidou, Ioanna

AU - Wheeler, Eleanor

AU - Zeggini, Eleftheria

AU - Al Turki, Saeed

AU - Anderson, Carl A.

AU - Antony, Dinu

AU - Beales, Phil

AU - Bentham, Jamie

AU - Bhattacharya, Shoumo

AU - Calissano, Mattia

AU - Carss, Keren

AU - Chatterjee, Krishna

AU - Cirak, Sebahattin

AU - Cosgrove, Catherine

AU - Durbin, Richard

AU - Fitzpatrick, David R.

AU - Floyd, James

AU - Foley, A. Reghan

AU - Franklin, Christopher S.

AU - Futema, Marta

AU - Grozeva, Detelina

AU - Humphries, Steve E.

AU - Hurles, Matthew E.

AU - McCarthy, Shane

AU - Mitchison, Hannah M.

AU - Muddyman, Dawn

AU - Muntoni, Francesco

AU - Onoufriadis, Alexandros

AU - Parker, Victoria

AU - Payne, Felicity

AU - Plagnol, Vincent

AU - Raymond, F. Lucy

AU - Roberts, Nicola

AU - Savage, David B.

AU - Scambler, Peter

AU - Schmidts, Miriam

AU - Schoenmakers, Nadia

AU - Semple, Robert K.

AU - Serra, Eva

AU - Spasic-Boskovic, Olivera

AU - Stevens, Elizabeth

AU - van Kogelenberg, Margriet

AU - Vijayarangakannan, Parthiban

AU - Walter, Klaudia

AU - Williamson, Kathleen A.

AU - Wilson, Crispian

AU - Whyte, Tamieka

AU - Ciampi, Antonio

AU - Greenwood, Celia M. T.

AU - Li, Rui

AU - Metrustry, Sarah

AU - Oualkacha, Karim

AU - Tachmazidou, Ioanna

AU - Xu, ChangJiang

AU - Zeggini, Eleftheria

AU - Bobrow, Martin

AU - Bolton, Patrick F.

AU - Durbin, Richard

AU - Fitzpatrick, David R.

AU - Griffin, Heather

AU - Hurles, Matthew E.

AU - Kaye, Jane

AU - Kennedy, Karen

AU - Kent, Alastair

AU - Muddyman, Dawn

AU - Muntoni, Francesco

AU - Fitzpatrick, David R.

AU - McCarthy, Shane

AU - Morris, Richard

PY - 2019/4/12

Y1 - 2019/4/12

N2 - 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.

AB - 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.

KW - LEPTIN RESISTANCE

KW - PROOPIOMELANOCORTIN NEURONS

KW - SIGNAL TRANSDUCER

KW - SOCS-3 EXPRESSION

KW - FOOD-INTAKE

KW - PPAR-GAMMA

KW - ER STRESS

KW - OBESITY

KW - BALANCE

KW - FOXO1

U2 - 10.1038/s41467-019-08737-6

DO - 10.1038/s41467-019-08737-6

M3 - Article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 1718

ER -