at the CNIC

Tag: liver (Page 1 of 13)

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.

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.

Programa CICERONE 2023 para estudiantes de Grado y Máster

Como en años anteriores, nuestro grupo ofrece dos plazas para que estudiantes de Grado y Máster realicen prácticas en nuestro laboratorio entre el 1 de julio y el 15 de septiembre de 2023.

El propósito del programa CICERONE es acercar la investigación biomédica a los estudiantes universitarios para que puedan escoger más adecuadamente su orientación profesional.

Para inscribirse es necesario crear una cuenta en la web del CNIC antes del 28 de abril de 2023.

Enlace Tamaño
Bases de la convocatoria 2023 243 KB
Extracto del BOE 167 KB

Los dos proyectos científicos que ofrecemos este año son:

  • Stress in the brain, metabolic effects: Obesity has become a new pandemic. It is known that obesity induces molecular changes in the brain that are fundamental for the development of diseases and for maintaining excess energy intake. However, little is known about how these changes appear and the molecular mechanisms that mediate them. We will study how modulating stress in the central nervous system induced by high fat diet affects the development of cardiometabolic diseases. For this purpose, genetically modified animals will be used and whole organism metabolism will be evaluated, and how the signalling of this stress in the brain affects the response of distant organs through inter-tissue communication.
  • Role of adipose tissue controling whole body homeostasis: Cardiometabolic diseases (CMDs)—e.g., diabetes, steatohepatitis, and cardiomyopathy— are the leading cause of death worldwide. Adipose tissue (AT) heterogeneity and dysfunction might be involved in the CMD pathogenesis. We have recently demonstrated that i) AT regulates whole-body metabolism independently of obesity and predisposes to hepatic cancer in mice and humans; and ii) molecules secreted by AT trigger liver steatosis and insulin resistance. Our studies suggest that dysfunctional AT communicates with other organs and induces pathogenic adaptive responses through evolutionarily conserved mechanisms (rodent to humans). Our preliminary results show that AT dysfunction caused by mitochondrial alteration induces cardiomyopathy in lean mice, reinforcing that AT has a central role in controlling heart functionality.
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