Tag: JNK1 (Page 1 of 2)

A hypothalamus-liver-skeletal muscle axis controlled by JNK1 and FGF21 mediates olanzapine-induced insulin resistance in an intraperitoneal treatment in male mice

21/07/2026 / Sabio lab

Vitor Ferreira, Cintia Folgueira, Ana B Hitos, Ángela Montes San-Lorenzo, Ánxela Estévez-Salguero, Begoña Porteiro, Roger J Davis, Miguel López, Guadalupe Sabio, Patricia Rada & Ángela M Valverde.

Olanzapine (OLA), a widely prescribed second-generation antipsychotic, is associated with adverse metabolic effects. We recently showed that oral OLA treatment in male mice induces weight gain and hepatic steatosis, whereas intraperitoneal (i.p.) administration leads to weight loss due to higher hypothalamic OLA levels and activation of brown adipose tissue. Since clinical studies report insulin resistance in individuals receiving OLA, here we investigated the impact of OLA i.p. treatment on insulin sensitivity, focusing on the liver-skeletal muscle axis.

Treatment with olanzapine reduces mice weight.

Wild-type (WT) male mice were treated with OLA (10 mg/kg, i.p.) for 8 weeks or received a single intrahypothalamic injection (15 nmol). Glucose homeostasis parameters were assessed. Mechanistic studies were performed in vagotomized mice, mice lacking JNK in either the hypothalamus or liver, mice overexpressing hepatic FGF21, and PTP1B-deficient mice (PTP1B-KO).

OLA i.p. treatment in WT mice induced systemic insulin resistance, pyruvate intolerance, and reduced insulin signaling in liver and skeletal muscle. These effects were accompanied by increased hepatic JNK phosphorylation and IRS1 serine phosphorylation. A single intrahypothalamic OLA injection similarly impaired peripheral insulin action and activated hepatic JNK. Deletion of hypothalamic or hepatic JNK1, as well as vagotomy, prevented these defects. OLA reduced hepatic Fgf21 expression, an effect reversed by hypothalamic JNK1 deletion or vagotomy. Hepatic FGF21 overexpression prevented OLA-induced insulin resistance in skeletal muscle, but not in liver. PTP1B-KO mice were protected from all OLA-induced metabolic impairments.

Although OLA i.p. treatment prevents weight gain, it decreases peripheral insulin sensitivity through a hypothalamus-liver axis driven by hypothalamic JNK1, which activates hepatic JNK via the vagus nerve, suppresses hepatic FGF21 and ultimately impairs insulin signaling in skeletal muscle. Importantly, the protection conferred by PTP1B deficiency against OLA-induced insulin resistance strongly suggests that targeting PTP1B might prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Redox Biol (2026); 95: 104286.

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.