JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism

Iara Fernández-González; Oscar Freire-Agulleiro; Vitor Ferreira; María Silveira-Loureiro; Eva Rial-Pensado; Pablo Garrido-Gil; Gloria Martínez; Patricia Rada; José L. Labandeira-García; Jens Mittag; Ismael González-García; Carlos Diéguez; Rubén Nogueiras; Ángela M. Valverde; Roger J. Davis; Guadalupe Sabio; Olga Barca-Mayo; Miguel López

doi:10.1016/j.molmet.2025.102170

JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism

Iara Fernández-González, Oscar Freire-Agulleiro, Vitor Ferreira, María Silveira-Loureiro, Eva Rial-Pensado, Pablo Garrido-Gil, Gloria Martínez, Patricia Rada, José L. Labandeira-García, Jens Mittag, Ismael González-García, Carlos Diéguez, Rubén Nogueiras, Ángela M. Valverde, Roger J. Davis, Guadalupe Sabio, Olga Barca-Mayo^*, Miguel López^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Experimentelle Endokrinologie

1 Zitat (Scopus)

Abstract

Objective: Hypothalamic energy sensors, such as AMP-activated protein kinase (AMPK), and stress sensors, such as c-Jun N-terminal kinase 1 (JNK1, also known as MAPK8) modulate whole body energy balance. While the role of AMPK in steroidogenic factor 1 (SF1) neurons of the VMH has been investigated, the relevance of JNK1 in this neuronal population has not been addressed. Here, we investigated the involvement of JNK1 SF1 on energy homeostasis. Methods: We generated mice bearing conditional JNK1 disruption through Mapk8 gene deletion in SF1 neurons (Sf1^Cre/Jnk1^fl/fl). Complete metabolic phenotyping, fasting/refeeding and cold challenges, as well as the central response to triiodothyronine (T3) on brown adipose tissue (BAT) thermogenesis and hepatic lipid metabolism were carried out. Results: Sf1^Cre/Jnk1^fl/fl mice displayed decreased body weight, improved glucose tolerance, and reduced hepatic lipid levels. However, Sf1^Cre/Jnk1^fl/fl did not properly defend their temperature upon cold exposure. While central administration of T3 elicited feeding independent weight loss in both wildtype (Jnk1^fl/fl) and SF1^Cre/Jnk1^fl/fl mice, it did not promote hepatic lipid accretion in null animals. Conclusions: Our data demonstrated for the first time that JNK1 in SF1 neurons is necessary for the regulation of hepatic lipid metabolism, cold adaptation and central T3 actions.

Originalsprache	Englisch
Aufsatznummer	102170
Zeitschrift	Molecular Metabolism
Jahrgang	98
Seiten (von - bis)	102170
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2025.102170
Publikationsstatus	Veröffentlicht - 08.2025

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The research leading to these results has received funding from the Xunta de Galicia (IG-G: ED431F 2024/14; IG-G and RN ED431C 2024/10; RN: 2016-PG057 ; OB-M: ED431F 2020/009 and ED431C 2023/28 ); Ministerio de Ciencia e Innovaci\u00F3n co-funded by the FEDER Program of EU (IG-G: PID2022-141115NA-I00 ; CD: PID2020-116628 GB-I00 ; RN: RTI2018-099413-B-I00 and RED2018-102379-T ; AM-V; PID2021-122766OB-100 ; GS: PID2019-104399RB-I00 ; PMP21/00057 ; PDC2021-121147-I00 IMPACT-202; OB-M: PID2019-109556RB-I00 ; PID2022-138436OB-I00 ; ML: PID2021-128145NB-I00 and PDC2022-133958-I00 ); European Research Council (RN: ERC Synergy Grant- 2019-WATCH- 810331 ); \u201Cla Caixa\u201D Foundation (ID 100010434 ), (ML: LCF/PR/HR19/52160022 and LCF/PR/HR20/52400013 ); Fundaci\u00F3n AECC (GS: PROYE19047SABI ; ML: PRYGN234908LOPE ). IG-G and OB-M are supported by Ram\u00F3n y Cajal Awards (IG-G: RYC2021-031225-I ; OB-M: RYC2018-026293-I ) from the Ministerio de Ciencia e Innovaci\u00F3n of Spain . OF-A was supported by a fellowship from Xunta de Galicia ( ED481A-2019/026 ). CiMUS was supported by the Xunta de Galicia (2020\u20132023, ED431G/05 ). CIBER de Fisiopatolog\u00EDa de la Obesidad y Nutrici\u00F3n, CIBER de Diabetes y Enfermedades Metab\u00F3licas Asociadas and CIBER de Enfermedades Neurodegenerativas are initiatives of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Träger	Trägernummer
Instituto de Salud Carlos III
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)
European Regional Development Fund	PID2019-109556RB-I00, PID2021-122766OB-100, PID2022-141115NA-I00, RTI2018-099413-B-I00, PMP21/00057, PID2020-116628 GB-I00, RED2018-102379-T, PDC2022-133958-I00
Fundación Científica Asociación Española Contra el Cáncer	RYC2018-026293-I, RYC2021-031225-I
Xunta de Galicia	ED431C 2023/28, 2016-PG057, ED431F 2020/009, RN ED431C 2024/10, ED431F 2024/14
Ministerio de Ciencia e Innovación	ED431G/05, ED481A-2019/026
European Research Council	2019-WATCH- 810331
'la Caixa' Foundation	LCF/PR/HR19/52160022, la Caixa” Foundation, LCF/PR/HR20/52400013

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10.1016/j.molmet.2025.102170

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Fernández-González, I., Freire-Agulleiro, O., Ferreira, V., Silveira-Loureiro, M., Rial-Pensado, E., Garrido-Gil, P., Martínez, G., Rada, P., Labandeira-García, J. L., Mittag, J., González-García, I., Diéguez, C., Nogueiras, R., Valverde, Á. M., Davis, R. J., Sabio, G., Barca-Mayo, O., & López, M. (2025). JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism. Molecular Metabolism, 98, 102170. Artikel 102170. https://doi.org/10.1016/j.molmet.2025.102170

@article{3ca0e132baf54c7f8c0fe5b760220ab9,

title = "JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism",

abstract = "Objective: Hypothalamic energy sensors, such as AMP-activated protein kinase (AMPK), and stress sensors, such as c-Jun N-terminal kinase 1 (JNK1, also known as MAPK8) modulate whole body energy balance. While the role of AMPK in steroidogenic factor 1 (SF1) neurons of the VMH has been investigated, the relevance of JNK1 in this neuronal population has not been addressed. Here, we investigated the involvement of JNK1 SF1 on energy homeostasis. Methods: We generated mice bearing conditional JNK1 disruption through Mapk8 gene deletion in SF1 neurons (Sf1Cre/Jnk1fl/fl). Complete metabolic phenotyping, fasting/refeeding and cold challenges, as well as the central response to triiodothyronine (T3) on brown adipose tissue (BAT) thermogenesis and hepatic lipid metabolism were carried out. Results: Sf1Cre/Jnk1fl/fl mice displayed decreased body weight, improved glucose tolerance, and reduced hepatic lipid levels. However, Sf1Cre/Jnk1fl/fl did not properly defend their temperature upon cold exposure. While central administration of T3 elicited feeding independent weight loss in both wildtype (Jnk1fl/fl) and SF1Cre/Jnk1fl/fl mice, it did not promote hepatic lipid accretion in null animals. Conclusions: Our data demonstrated for the first time that JNK1 in SF1 neurons is necessary for the regulation of hepatic lipid metabolism, cold adaptation and central T3 actions.",

author = "Iara Fern{\'a}ndez-Gonz{\'a}lez and Oscar Freire-Agulleiro and Vitor Ferreira and Mar{\'i}a Silveira-Loureiro and Eva Rial-Pensado and Pablo Garrido-Gil and Gloria Mart{\'i}nez and Patricia Rada and Labandeira-Garc{\'i}a, \{Jos{\'e} L.\} and Jens Mittag and Ismael Gonz{\'a}lez-Garc{\'i}a and Carlos Di{\'e}guez and Rub{\'e}n Nogueiras and Valverde, \{{\'A}ngela M.\} and Davis, \{Roger J.\} and Guadalupe Sabio and Olga Barca-Mayo and Miguel L{\'o}pez",

year = "2025",

month = aug,

doi = "10.1016/j.molmet.2025.102170",

language = "English",

volume = "98",

pages = "102170",

journal = "Molecular Metabolism",

issn = "2212-8778",

}

Fernández-González, I, Freire-Agulleiro, O, Ferreira, V, Silveira-Loureiro, M, Rial-Pensado, E, Garrido-Gil, P, Martínez, G, Rada, P, Labandeira-García, JL, Mittag, J, González-García, I, Diéguez, C, Nogueiras, R, Valverde, ÁM, Davis, RJ, Sabio, G, Barca-Mayo, O & López, M 2025, 'JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism', Molecular Metabolism, Jg. 98, 102170, S. 102170. https://doi.org/10.1016/j.molmet.2025.102170

TY - JOUR

T1 - JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism

AU - Fernández-González, Iara

AU - Freire-Agulleiro, Oscar

AU - Ferreira, Vitor

AU - Silveira-Loureiro, María

AU - Rial-Pensado, Eva

AU - Garrido-Gil, Pablo

AU - Martínez, Gloria

AU - Rada, Patricia

AU - Labandeira-García, José L.

AU - Mittag, Jens

AU - González-García, Ismael

AU - Diéguez, Carlos

AU - Nogueiras, Rubén

AU - Valverde, Ángela M.

AU - Davis, Roger J.

AU - Sabio, Guadalupe

AU - Barca-Mayo, Olga

AU - López, Miguel

PY - 2025/8

Y1 - 2025/8

N2 - Objective: Hypothalamic energy sensors, such as AMP-activated protein kinase (AMPK), and stress sensors, such as c-Jun N-terminal kinase 1 (JNK1, also known as MAPK8) modulate whole body energy balance. While the role of AMPK in steroidogenic factor 1 (SF1) neurons of the VMH has been investigated, the relevance of JNK1 in this neuronal population has not been addressed. Here, we investigated the involvement of JNK1 SF1 on energy homeostasis. Methods: We generated mice bearing conditional JNK1 disruption through Mapk8 gene deletion in SF1 neurons (Sf1Cre/Jnk1fl/fl). Complete metabolic phenotyping, fasting/refeeding and cold challenges, as well as the central response to triiodothyronine (T3) on brown adipose tissue (BAT) thermogenesis and hepatic lipid metabolism were carried out. Results: Sf1Cre/Jnk1fl/fl mice displayed decreased body weight, improved glucose tolerance, and reduced hepatic lipid levels. However, Sf1Cre/Jnk1fl/fl did not properly defend their temperature upon cold exposure. While central administration of T3 elicited feeding independent weight loss in both wildtype (Jnk1fl/fl) and SF1Cre/Jnk1fl/fl mice, it did not promote hepatic lipid accretion in null animals. Conclusions: Our data demonstrated for the first time that JNK1 in SF1 neurons is necessary for the regulation of hepatic lipid metabolism, cold adaptation and central T3 actions.

AB - Objective: Hypothalamic energy sensors, such as AMP-activated protein kinase (AMPK), and stress sensors, such as c-Jun N-terminal kinase 1 (JNK1, also known as MAPK8) modulate whole body energy balance. While the role of AMPK in steroidogenic factor 1 (SF1) neurons of the VMH has been investigated, the relevance of JNK1 in this neuronal population has not been addressed. Here, we investigated the involvement of JNK1 SF1 on energy homeostasis. Methods: We generated mice bearing conditional JNK1 disruption through Mapk8 gene deletion in SF1 neurons (Sf1Cre/Jnk1fl/fl). Complete metabolic phenotyping, fasting/refeeding and cold challenges, as well as the central response to triiodothyronine (T3) on brown adipose tissue (BAT) thermogenesis and hepatic lipid metabolism were carried out. Results: Sf1Cre/Jnk1fl/fl mice displayed decreased body weight, improved glucose tolerance, and reduced hepatic lipid levels. However, Sf1Cre/Jnk1fl/fl did not properly defend their temperature upon cold exposure. While central administration of T3 elicited feeding independent weight loss in both wildtype (Jnk1fl/fl) and SF1Cre/Jnk1fl/fl mice, it did not promote hepatic lipid accretion in null animals. Conclusions: Our data demonstrated for the first time that JNK1 in SF1 neurons is necessary for the regulation of hepatic lipid metabolism, cold adaptation and central T3 actions.

UR - https://www.scopus.com/pages/publications/105007422529

UR - https://www.mendeley.com/catalogue/0352acb0-cc70-33a8-810d-ded1644a221d/

U2 - 10.1016/j.molmet.2025.102170

DO - 10.1016/j.molmet.2025.102170

M3 - Journal articles

C2 - 40419019

AN - SCOPUS:105007422529

SN - 2212-8778

VL - 98

SP - 102170

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 102170

ER -

JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism

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