Fernández-González Iara, Freire-Agulleiro Oscar, Ferreira Vitor, Silveira-Loureiro María, Rial-Pensado Eva, Garrido-Gil Pablo, Martínez Gloria, Rada Patricia, Labandeira-García José L, Mittag Jens, González-García Ismael, Diéguez Carlos, Nogueiras Rubén, Valverde Ángela M, Davis Roger J, Sabio Guadalupe, Barca-Mayo Olga, López Miguel
Department of Physiology, CiMUS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain.
Department of Physiology, CiMUS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain; Instituto de Investigaciones Biomedicas Sols-Morreale (IIBM), CSIC-UAM, 28029, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, 28029, Madrid, Spain.
Mol Metab. 2025 May 24;98:102170. doi: 10.1016/j.molmet.2025.102170.
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.
We generated mice bearing conditional JNK1 disruption through Mapk8 gene deletion in SF1 neurons (Sf1/Jnk1). 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.
Sf1/Jnk1 mice displayed decreased body weight, improved glucose tolerance, and reduced hepatic lipid levels. However, Sf1/Jnk1 did not properly defend their temperature upon cold exposure. While central administration of T3 elicited feeding independent weight loss in both wildtype (Jnk1) and SF1/Jnk1 mice, it did not promote hepatic lipid accretion in null animals.
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.
下丘脑能量传感器，如AMP激活的蛋白激酶（AMPK），以及应激传感器，如c-Jun氨基末端激酶1（JNK1，也称为MAPK8），调节全身能量平衡。虽然已经研究了AMPK在腹内侧下丘脑（VMH）类固醇生成因子1（SF1）神经元中的作用，但JNK1在该神经元群体中的相关性尚未得到探讨。在此，我们研究了JNK1 SF1在能量稳态中的作用。
我们通过在SF1神经元中缺失Mapk8基因产生了条件性JNK1缺失的小鼠（Sf1/Jnk1）。进行了完整的代谢表型分析、禁食/再喂养和冷刺激实验，以及三碘甲状腺原氨酸（T3）对棕色脂肪组织（BAT）产热和肝脏脂质代谢的中枢反应实验。
Sf1/Jnk1小鼠体重下降，葡萄糖耐受性改善，肝脏脂质水平降低。然而，Sf1/Jnk1小鼠在冷暴露时不能正常维持体温。虽然中枢给予T3在野生型（Jnk1）和SF1/Jnk1小鼠中均引起了与进食无关的体重减轻，但在基因敲除动物中它并未促进肝脏脂质堆积。
我们的数据首次证明，SF1神经元中的JNK1对于肝脏脂质代谢、冷适应和中枢T3作用的调节是必需的。
