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Author: Sabio lab (Page 1 of 41)

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

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.

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.

La Asociación Europea del Estudio de la Obesidad y la Fundación Novo Nordisk premian a Cintia Folgueira

Nuestra compañera Cintia Folgueira Cobos ha sido galardonada con el premio de la Asociación Europea del Estudio de la Obesidad y la Fundación Novo Nordisk en la categoría de Ciencias Básicas por su excelencia y compromiso.

El premio implica la concesión de una subvención de unos 40.000 euros y la participación de la Dra. Folgueira en el Congreso Europeo de la Obesidad, el 18 de este mes en Dublín. “Gracias a este reconocimiento conseguiremos identificar de manera más precisa los mecanismos moleculares que controlan la funcionalidad del tejido adiposo y la secreción de biomoléculas por el tejido adiposo, lo que podría resultar en el desarrollo de nuevos fármacos para combatir la obesidad y sus comorbilidades”, asegura.

Entre otros proyectos, la Dra. Folgueira está involucrada en el metabolismo del tejido adiposo y su función endocrina y termogénica.  “Mientras que el tejido adiposo blanco es un sitio de almacenamiento de energía, el tejido adiposo marrón disipa energía y es responsable de la termogénesis. Es en este tejido adiposo marrón y en este proceso de generación de calor (termogénesis) donde las mitocondrias son un componente central del consumo de energía y necesitan adaptarse a los cambios en las demandas energéticas: la activación mitocondrial es clave para regular la termogénesis”.

La importancia de las mitocondrias de la grasa

Sus investigaciones han encontrado que una proteína mitocondrial específica está disminuida en el tejido adiposo de pacientes obesos en comparación con individuos delgados. “En estudios con roedores, encontramos una disminución en el peso corporal y un aumento de la termogénesis cuando nuestros ratones son alimentados con dieta alta en grasa. Además, observamos que esta proteína está alterada después de la exposición al frío, lo que nos sugiere que puede controlar la termogénesis en el tejido adiposo marrón, lo que abre una ventana terapéutica para la prevención de la obesidad al modular su expresión”.

Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation

Osman Ahmed, April S. Caravaca, María Crespo, Wanmin Dai, Ting Liu, Qi Guo , Magdalena Leiva, Guadalupe Sabio, Vladimir S. Shavva, Stephen G. Malin & Peder S. Olofsson.

The liver is an important immunological organ and liver inflammation is part of the pathophysiology of non-alcoholic steatohepatitis, a condition that may promote cirrhosis, liver cancer, liver failure, and cardiovascular disease. Despite dense innervation of the liver parenchyma, little is known about neural regulation of liver function in inflammation. Here, we study vagus nerve control of the liver response to acute inflammation.

Detection by FACS of activated hepatic stellate cells (Image: María Crespo).

Methods: Male C57BL/6 J mice were subjected to either sham surgery, surgical vagotomy, or electrical vagus nerve stimulation followed by intraperitoneal injection of the TLR2 agonist zymosan. Animals were euthanized and tissues collected 12 h after injection. Samples were analyzed by qPCR, RNAseq, flow cytometry, or ELISA.

Results: Hepatic mRNA levels of pro-inflammatory mediators Ccl2, Il-1β, and Tnf-α were significantly higher in vagotomized mice compared with mice subjected to sham surgery. Differences in liver Ccl2 levels between treatment groups were largely reflected in the plasma chemokine (C-C motif) ligand 2 (CCL2) concentration. In line with this, we observed a higher number of macrophages in the livers of vagotomized mice compared with sham as measured by flow cytometry. In mice subjected to electrical vagus nerve stimulation, hepatic mRNA levels of Ccl2, Il1β, and Tnf-α, and plasma CCL2 levels, were significantly lower compared with sham. Interestingly, RNAseq revealed that a key activation marker for hepatic stellate cells (HSC), Pnpla3, was the most significantly differentially expressed gene between vagotomized and sham mice. Of note, several HSC-activation associated transcripts were higher in vagotomized mice, suggesting that signals in the vagus nerve contribute to HSC activation. In support of this, we observed significantly higher number of activated HSCs in vagotomized mice as compared with sham as measured by flow cytometry.

Conclusions: Signals in the cervical vagus nerve controlled hepatic inflammation and markers of HSC activation in zymosan-induced peritonitis.

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