Tag: JNK1 (Page 1 of 2)

Attack of the kinases: JNK signaling in metabolism

13/03/2026 / Sabio lab

Iara Fernández-González, Jane Jose Vattathara, Roger J. Davis, Guadalupe Sabio & Miguel López.

The global rise in obesity has become a major health concern, in part due to the easy availability and consumption of high-calorie foods together with an increasingly sedentary lifestyle.

More than a mere consequence of excess fat accumulation, obesity is now considered a complex health issue involving disrupted balance in how the body manages energy, primarily due to miscommunication between brain regions, such as the hypothalamus, and peripheral organs. One important aspect of this problem is how specific cell signaling pathways are disrupted by aberrant energy sensing and by oxidative stress-mediated damage and inflammation. Among these, AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) have gained wide attention as key players that integrate nutrient-, hormone- and inflammation-related signals.

Here, we provide a comprehensive review of isoform-specific JNK functions, highlighting recent advances in the understanding of JNK1, JNK2 and JNK3 in hypothalamic circuits that govern energy balance, thermogenesis and hepatic lipid metabolism. In addition, we also highlight the evolutionary and physiological significance of these kinase isoforms. Thus, this review encompasses current knowledge and key unanswered questions regarding the role of JNK in central and peripheral metabolic regulation.

Am J Physiol Regul Integr Comp Physiol. 2026 Feb 23. doi: 10.1152/ajpregu.00286.2025.

Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition

26/05/2023 / Sabio lab

Vitor Ferreira, Cintia Folgueira, María García-Altares, Maria Guillén, Mónica Ruíz-Rosario, Giada DiNunzio, Irma Garcia-Martinez, Rosa Alen, Christoph Bookmeyer, John G. Jones, Juan C. Cigudosa, Pilar López-Larrubia, Xavier Correig-Blanchar, Roger J. Davis, Guadalupe Sabio, Patricia Rada & Ángela M. Valverde.

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p.

Olanzapine iniection increases hypothalamic JNK phosphorylation (Imagen: Cintia Folgueira).

Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis.

The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Redox Biol. 2023; 63: 102741.

Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function

27/09/2021 / Sabio lab

Natáliada Silva Lima, Marcos F. Fondevila, Eva Nóvoa, Xabier Buqué, Maria Mercado-Gómez, Sarah Gallet, Maria J. González-Rellan, Uxia Fernandez, Anne Loyens, Maria Garcia-Vence, Maria del Pilar Chantada-Vazquez, Susana B. Bravo, Patricia Marañon, Ana Senra, Adriana Escudero, Magdalena Leiva, Diana Guallar, Miguel Fidalgo, Pedro Gomes, Marc Claret, Guadalupe Sabio, Marta Varela-Rey, Teresa C. Delgado, Rocio Montero-Vallejo, Javier Ampuero, Miguel López, Carlos Diéguez, Laura Herrero, Dolors Serra, Markus Schwaninger, Vincent Prevo, Rocio Gallego-Duran, Manuel Romero-Gomez, Paula Iruzubieta, Javier Crespo, Maria L. Martinez-Chantar, Carmelo Garcia-Monzon, Agueda Gonzalez-Rodriguez, Patricia Aspichueta & Ruben Nogueiras.

BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to nonalcoholic fatty liver disease (NAFLD) remains unknown.

METHODS: By performing a liver proteomic analysis from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples of patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the liver of mice.

JNK1 inhibitor SP600125 blunted increased lipid content (Image: Magdalena Leiva).

RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and NASH) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoiltransferase I (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action.

CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis.

Hepatology 2021: doi:10.1002/hep.32149.