RT Journal Article
T1 Kappa-opioid receptor blockade ameliorates obesity caused by estrogen withdrawal via promotion of energy expenditure through mTOR pathway
A1 Romero Picó, Amparo
A1 Garrido Novelle, Marta
A1 Al-Massadi, Omar
A1 Beiroa, Daniel
A1 Tojo, Marta
A1 Heras, Violeta
A1 Ruíz Pino, Francisco
A1 Senra, Ana
A1 López, Miguel
A1 Blouet, Clemence
A1 Tena Sempere, Manuel
A1 Nogueiras, Rubén
A1 Diéguez, Carlos
AB Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the kappa-opioid receptor (k-OR) system is involved in mediating body weight changes associated with E2 withdrawal. Here, we document that body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1−/−global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating weight gain and adiposity in OVX mice. These findings will help to define new therapies to manage metabolic disorders associated with low/null E2 levels based on the modulation of central k-OR signaling.
SN 1661-6596
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/94507
UL https://hdl.handle.net/20.500.14352/94507
LA eng
NO Romero-Picó, A.; Novelle, M.G.; Al-Massadi, O.; Beiroa, D.; Tojo, M.; Heras, V.; Ruiz-Pino, F.; Senra, A.; López, M.; Blouet, C.; et al. Kappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway. Int. J. Mol. Sci. 2022, 23, 3118. https://doi.org/10.3390/ijms23063118
NO This work has been supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (CD: PID2020-116628GB-I00; MTS: BFU2017-83934-P; RN: RTI2018-099413-B-I00; ML: RTI2018-101840-B-I00 and ML: BFU2017-90578-REDT/Adipoplast) and Instituto de Salud Carlos III-European Union (OA-M: PI21/01216). The research leading to these results has also received funding from Atresmedia Corporación (RN and ML); Fundación BBVA (RN); “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR19/52160022 (ML); European Foundation for the Study of Diabetes (RN), Fundación de la Sociedad Gallega de Endocrinología y Nutrición (OA-M) and ERC Synergy Grant-2019-WATCH-810331 (RN). Financial support from the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019–2022-ED431G 2019/02) and the European Union (European Regional Development Fund—ERDF) is gratefully acknowledged. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by ERDF funds. MGN is recipient of “Juan de la Cierva-Incorporación” fellowship (IJCI-2017-32606) from Ministerio de Ciencia, Innovación y Universidades, Spain. OA-M was funded by a research contract Miguel Servet (CP20/00146) from the ISCIII.
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO European Commission
NO Instituto de Salud Carlos III
NO Fundación BBVA
NO Fundación La Caixa
NO Xunta de Galicia
DS Docta Complutense
RD 26 feb 2026