mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol

Ismael González-García; Pablo B Martinez de Morentin; Ánxela  Estévez-Salguero; Cristina Contreras; Amparo  Romero-Picó; Johan Fernø; Ruben Nogueiras; Carlos Diéguez; Manuel  Tena-Sempere; Sulay Tovar; Miguel López

doi:10.1530/JOE-18-0190

mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol

Ismael González-García, Pablo B Martinez de Morentin, Ánxela Estévez-Salguero, Cristina Contreras, Amparo Romero-Picó , Johan Fernø, Ruben Nogueiras, Carlos Diéguez, Manuel Tena-Sempere, Sulay Tovar, Miguel López

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

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Abstract

Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that, ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC

Original language	English
Pages (from-to)	177-186
Number of pages	9
Journal	Journal of Endocrinology
Volume	238
Issue number	3
Early online date	18 Jun 2018
DOIs	https://doi.org/10.1530/JOE-18-0190
Publication status	Published - Sept 2018

Bibliographical note

The authors dedicate this work to the bright memory of our colleague,
master and friend Enrique Aguilar. The research leading to these results
has received funding from Xunta de Galicia (R N: 2015-CP080 and 2016-
PG057; M L: 2015-CP079), Junta de Andalucía (M T-S: P12-FQM-01943),
MINECO co-funded by the FEDER Program of EU (C D: BFU2017-87721; R N:
BFU2015-70664R; M T-S: BFU2014-57581-P and PIE14/0005; M L: SAF2015-
71026-R and BFU2015-70454-REDT/Adipoplast). The CiMUS is supported
by the Xunta de Galicia (2016–2019, ED431G/05). CIBER Fisiopatología
de la Obesidad y Nutrición is an initiative of ISCIII. A E-S is a recipient of
a fellowship from MINECO (FPI/BES-2016-077439). The funders had no
role in study design, data collection and analysis, decision to publish or
preparation of the manuscript.

Keywords

estradiol
hypothalamus
food intake
mTOR
obesity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol
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Cite this

González-García, I., Martinez de Morentin, P. B., Estévez-Salguero, Á., Contreras, C., Romero-Picó , A., Fernø, J., Nogueiras, R., Diéguez, C., Tena-Sempere, M., Tovar, S., & López, M. (2018). mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol. Journal of Endocrinology, 238(3), 177-186. https://doi.org/10.1530/JOE-18-0190

González-García, I, Martinez de Morentin, PB, Estévez-Salguero, Á, Contreras, C, Romero-Picó , A, Fernø, J, Nogueiras, R, Diéguez, C, Tena-Sempere, M, Tovar, S & López, M 2018, 'mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol', Journal of Endocrinology, vol. 238, no. 3, pp. 177-186. https://doi.org/10.1530/JOE-18-0190

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title = "mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol",

abstract = "Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that, ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC",

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author = "Ismael Gonz{\'a}lez-Garc{\'i}a and {Martinez de Morentin}, {Pablo B} and {\'A}nxela Est{\'e}vez-Salguero and Cristina Contreras and Amparo Romero-Pic{\'o} and Johan Fern{\o} and Ruben Nogueiras and Carlos Di{\'e}guez and Manuel Tena-Sempere and Sulay Tovar and Miguel L{\'o}pez",

note = "The authors dedicate this work to the bright memory of our colleague, master and friend Enrique Aguilar. The research leading to these results has received funding from Xunta de Galicia (R N: 2015-CP080 and 2016- PG057; M L: 2015-CP079), Junta de Andaluc{\'i}a (M T-S: P12-FQM-01943), MINECO co-funded by the FEDER Program of EU (C D: BFU2017-87721; R N: BFU2015-70664R; M T-S: BFU2014-57581-P and PIE14/0005; M L: SAF2015- 71026-R and BFU2015-70454-REDT/Adipoplast). The CiMUS is supported by the Xunta de Galicia (2016–2019, ED431G/05). CIBER Fisiopatolog{\'i}a de la Obesidad y Nutrici{\'o}n is an initiative of ISCIII. A E-S is a recipient of a fellowship from MINECO (FPI/BES-2016-077439). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.",

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AU - González-García, Ismael

AU - Martinez de Morentin, Pablo B

AU - Estévez-Salguero, Ánxela

AU - Contreras, Cristina

AU - Romero-Picó , Amparo

AU - Fernø, Johan

AU - Nogueiras, Ruben

AU - Diéguez, Carlos

AU - Tena-Sempere, Manuel

AU - Tovar, Sulay

AU - López, Miguel

N1 - The authors dedicate this work to the bright memory of our colleague, master and friend Enrique Aguilar. The research leading to these results has received funding from Xunta de Galicia (R N: 2015-CP080 and 2016- PG057; M L: 2015-CP079), Junta de Andalucía (M T-S: P12-FQM-01943), MINECO co-funded by the FEDER Program of EU (C D: BFU2017-87721; R N: BFU2015-70664R; M T-S: BFU2014-57581-P and PIE14/0005; M L: SAF2015- 71026-R and BFU2015-70454-REDT/Adipoplast). The CiMUS is supported by the Xunta de Galicia (2016–2019, ED431G/05). CIBER Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. A E-S is a recipient of a fellowship from MINECO (FPI/BES-2016-077439). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

PY - 2018/9

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N2 - Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that, ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC

AB - Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that, ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC

KW - estradiol

KW - hypothalamus

KW - food intake

KW - mTOR

KW - obesity

U2 - 10.1530/JOE-18-0190

DO - 10.1530/JOE-18-0190

M3 - Article

SN - 0022-0795

VL - 238

SP - 177

EP - 186

JO - Journal of Endocrinology

JF - Journal of Endocrinology

IS - 3

ER -

mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol

Abstract

Bibliographical note

Keywords

UN SDGs

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