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Kappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway.

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cam.issuedOnline2022-03-14
dc.contributor.authorRomero-Picó, Amparo
dc.contributor.authorNovelle, Marta G
dc.contributor.authorAl-Massadi, Omar
dc.contributor.authorBeiroa, Daniel
dc.contributor.authorTojo, Marta
dc.contributor.authorHeras, Violeta
dc.contributor.authorRuiz-Pino, Francisco
dc.contributor.authorSenra, Ana
dc.contributor.authorLópez, Miguel
dc.contributor.authorBlouet, Clemence
dc.contributor.authorTena-Sempere, Manuel
dc.contributor.authorNogueiras, Rubén
dc.contributor.authorDiéguez, Carlos
dc.contributor.orcidRomero-Picó, Amparo [0000-0001-5104-6998]
dc.contributor.orcidNovelle, Marta G [0000-0003-0285-7182]
dc.contributor.orcidAl-Massadi, Omar [0000-0003-0645-6159]
dc.contributor.orcidHeras, Violeta [0000-0002-0337-1662]
dc.contributor.orcidLópez, Miguel [0000-0002-7823-1648]
dc.contributor.orcidNogueiras, Rubén [0000-0002-9976-9930]
dc.date.accessioned2022-06-07T08:10:30Z
dc.date.available2022-06-07T08:10:30Z
dc.date.issued2022-03-14
dc.date.updated2022-06-07T08:10:29Z
dc.description.abstractWeight 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.
dc.identifier.doi10.17863/CAM.85146
dc.identifier.eissn1422-0067
dc.identifier.issn1661-6596
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337737
dc.languageen
dc.language.isoeng
dc.publisherMDPI AG
dc.publisher.urlhttp://dx.doi.org/10.3390/ijms23063118
dc.subjectenergy expenditure
dc.subjectestrogens
dc.subjectkappa-opioid
dc.subjectobesity
dc.subjectp70S6K
dc.subjectAdipose Tissue, Brown
dc.subjectAnimals
dc.subjectBody Weight
dc.subjectEating
dc.subjectEnergy Metabolism
dc.subjectEstrogens
dc.subjectFemale
dc.subjectHumans
dc.subjectMice
dc.subjectObesity
dc.subjectOvariectomy
dc.subjectReceptors, Opioid, kappa
dc.subjectTOR Serine-Threonine Kinases
dc.subjectWeight Gain
dc.titleKappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway.
dc.typeArticle
dcterms.dateAccepted2022-03-11
prism.issueIdentifier6
prism.publicationNameInt J Mol Sci
prism.volume23
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3390/ijms23063118

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