RESUMEN
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.
Asunto(s)
Hígado Graso , Transducción de Señal , Masculino , Animales , Ratones , Olanzapina/metabolismo , Transducción de Señal/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Quinasas Activadas por AMP/metabolismo , Hígado/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/genética , Hígado Graso/prevención & control , Ratones Noqueados , Inflamación/metabolismo , Ácido Graso Sintasas/metabolismo , Aumento de Peso , Hipotálamo/metabolismo , Ratones Endogámicos C57BLRESUMEN
Low-pressure photoionization (LPPI) is a versatile tool for the mass spectrometric detection of (semi-)volatile organic compounds, (s)VOC. Here, a dual-ion funnel MALDI/ESI ion injector was equipped with a direct-inlet LPPI module. A radio-frequency (RF) drive enabled the implementation of three Kr discharge lamps in a novel design optimized for efficient photoionization and undisturbed ion trajectories. Supported by expansion and collisional cooling and, optionally, dopant vapor, primarily intact radical ions and protonated molecules were generated. Molecular identification was supported by the high-resolving power of an Orbitrap mass analyzer. In our proof-of-concept study, exhaled human breath and head-space sampled coffee grounds were characterized with this high-throughput technique. From breath, a few hundred and for the coffee roasts more than thousand distinct (s)VOC features were recorded. Principal component analysis enabled the differentiation of coffee grounds by origin and roasting protocol.