RESUMEN
It has been suggested that interleukin-6 (IL-6) produced by adipocytes in obesity leads to liver insulin resistance, although this hypothesis has never been definitively tested. Accordingly, we did so by generating adipocyte-specific IL-6-deficient (AdipoIL-6-/-) mice and studying them in the context of diet-induced and genetic obesity. Mice carrying two floxed alleles of IL-6 (C57Bl/6J) were crossed with Cre recombinase-overexpressing mice driven by the adiponectin promoter to generate AdipoIL-6-/- mice. AdipoIL-6-/- and floxed littermate controls were fed a standard chow or high-fat diet (HFD) for 16 wk and comprehensively metabolically phenotyped. In addition to a diet-induced obesity model, we also examined the role of adipocyte-derived IL-6 in a genetic model of obesity and insulin resistance by crossing the AdipoIL-6-/- mice with leptin-deficient (ob/ob) mice. As expected, mice on HFD and ob/ob mice displayed marked weight gain and increased fat mass compared with chow-fed and ob/+ (littermate control) animals, respectively. However, deletion of IL-6 from adipocytes in either model had no effect on glucose tolerance or fasting hyperinsulinemia. We concluded that adipocyte-specific IL-6 does not contribute to whole body glucose intolerance in obese mice.
Asunto(s)
Adipocitos/metabolismo , Intolerancia a la Glucosa/genética , Interleucina-6/genética , Obesidad/genética , Aumento de Peso/genética , Adiponectina/biosíntesis , Adiponectina/genética , Adiposidad/genética , Animales , Composición Corporal/genética , Dieta Alta en Grasa , Intolerancia a la Glucosa/etiología , Resistencia a la Insulina/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/complicaciones , Obesidad/metabolismoRESUMEN
Frontotemporal dementia (FTD) is a neurodegenerative disorder that affects the frontal and temporal lobes of the brain, primarily in individuals under 65 years of age, and is the second most common form of dementia worldwide. There is no cure for FTD and current treatments offer limited symptomatic relief. Regular physical activity exhibits cognitive and neuroprotective benefits in healthy individuals and in various neurodegenerative diseases, such as Alzheimer's disease, but few studies have examined its efficacy in FTD. Accordingly, we investigated the impact of voluntary exercise training (VET) on the metabolic and behavioral characteristics of the rTg4510 transgenic mouse model of familial FTD. We show that regardless of genotype, VET increased energy expenditure, decreased sleep duration, and improved long-term memory in rTg4510 mice and WT littermates. Moreover, VET appeared to improve hyperactivity, a common feature of FTD, in rTg4510 mice. Although further work is required, these findings provide important insights into the potential benefits of physical activity in FTD.
Asunto(s)
Enfermedad de Alzheimer , Demencia Frontotemporal , Ratones , Animales , Demencia Frontotemporal/genética , Demencia Frontotemporal/terapia , Ratones Transgénicos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Lóbulo Temporal , Modelos Animales de Enfermedad , Ejercicio FísicoRESUMEN
The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Animales , Ratones , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/prevención & control , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/prevención & control , Hepatocitos , Inflamación/tratamiento farmacológicoRESUMEN
Adipose tissue macrophages (ATMs) display tremendous heterogeneity depending on signals in their local microenvironment and contribute to the pathogenesis of obesity. The phosphoinositide 3-kinase (PI3K) signalling pathway, antagonized by the phosphatase and tensin homologue (PTEN), is important for metabolic responses to obesity. We hypothesized that fluctuations in macrophage-intrinsic PI3K activity via PTEN could alter the trajectory of metabolic disease by driving distinct ATM populations. Using mice harbouring macrophage-specific PTEN deletion or bone marrow chimeras carrying additional PTEN copies, we demonstrate that sustained PI3K activity in macrophages preserves metabolic health in obesity by preventing lipotoxicity. Myeloid PI3K signalling promotes a beneficial ATM population characterized by lipid uptake, catabolism and high expression of the scavenger macrophage receptor with collagenous structure (MARCO). Dual MARCO and myeloid PTEN deficiencies prevent the generation of lipid-buffering ATMs, reversing the beneficial actions of elevated myeloid PI3K activity in metabolic disease. Thus, macrophage-intrinsic PI3K signalling boosts metabolic health by driving ATM programmes associated with MARCO-dependent lipid uptake.
Asunto(s)
Tejido Adiposo/metabolismo , Metabolismo de los Lípidos/genética , Macrófagos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores Inmunológicos/metabolismo , Transducción de Señal , Adipocitos/patología , Tejido Adiposo/patología , Animales , Trasplante de Médula Ósea , Diferenciación Celular , Quimera , Prueba de Tolerancia a la Glucosa , Lipidómica , Macrófagos/patología , Enfermedades Metabólicas/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/patología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Receptores Inmunológicos/genética , Transducción de Señal/genéticaRESUMEN
Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognizing that many circulating proteins are packaged in extracellular vesicles (EVs), we employed quantitative proteomic techniques to characterize the exercise-induced secretion of EV-contained proteins. Following a 1-hr bout of cycling exercise in healthy humans, we observed an increase in the circulation of over 300 proteins, with a notable enrichment of several classes of proteins that compose exosomes and small vesicles. Pulse-chase and intravital imaging experiments suggested EVs liberated by exercise have a propensity to localize in the liver and can transfer their protein cargo. Moreover, by employing arteriovenous balance studies across the contracting human limb, we identified several novel candidate myokines, released into circulation independently of classical secretion. These data identify a new paradigm by which tissue crosstalk during exercise can exert systemic biological effects.