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Título: | 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 | Autor: | Ferreira, Vitor Folgueira, Cintia García-Altares, María Guillén, Maria Ruíz-Rosario, Mónica DiNunzio, Giada Garcia-Martinez, Irma Alen, Rosa Bookmeyer, Christoph Jones, John G. Cigudosa, Juan C. López-Larrubia, Pilar Correig-Blanchar, Xavier Davis, Roger J. Sabio, Guadalupe Rada, Patricia Valverde, Angela M. |
Palavras-chave: | Olanzapine; Hypothalamus; Inter-organ crosstalk; Metabolic side-effects; Liver; PTP1B | Data: | Jul-2023 | Editora: | Elsevier | Projeto: | This work was funded by grants PID-2021-122766OB-100 (to AMV), PID2019-104399RB-I00 (to GS) and RTI2018-096061-B-I00 (to XCB) funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” by the European Union. We also acknowledge grants H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement 721236, European Commission), P2022/BMD-7227 (Comunidad de Madrid, Spain), Fundaci´on Ram´on Areces (Spain) and CIBERdem (ISCIII, Spain) to AMV. VF was a recipient of a contract from ITNTREATMENT and is currently a PhD fellow from the Portuguese Foundation for Science and Technology (2020.08388.BD, FCT, Portugal)/ ERDF. CF was awarded with Sara Borrell contract (CD19/00078, ISCIII, Spain). MGA has a postdoctoral contract 2018 BP 00188 funded by AGAUR (Spain), while CB is recipient of a postdoctoral contract from HORIZON-MSCA-2021-PF-01 MASS2 (Proposal number 101067953). | Título da revista, periódico, livro ou evento: | Redox Biology | Volume: | 63 | Resumo: | 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. | URI: | https://hdl.handle.net/10316/112593 | ISSN: | 22132317 | DOI: | 10.1016/j.redox.2023.102741 | Direitos: | openAccess |
Aparece nas coleções: | I&D CNC - Artigos em Revistas Internacionais |
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