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.