RESUMEN
A high-fat diet (HFD) is a well-known contributing factor in the development of obesity. Most rats fed HFDs become obese. Those that avoid obesity when fed HFDs are considered diet resistant (DR). We performed a microarray screen to identify genes specific to the mesenteric fat of DR rats and revealed high expression of guanylin and guanylyl cyclase C (GC-C) in some subjects. Our histologic studies revealed that the cellular source of guanylin and GC-C is macrophages. Therefore, we developed double-transgenic (Tg) rats overexpressing guanylin and GC-C in macrophages and found that they were resistant to the effects of HFDs. In the mesenteric fat of HFD-fed Tg rats, Fas and perilipin mRNAs were downregulated, and those of genes involved in fatty acid oxidation were upregulated, compared with the levels in HFD-fed wild-type rats. In vitro studies demonstrated that lipid accumulation was markedly inhibited in adipocytes cocultured with macrophages expressing guanylin and GC-C and that this inhibition was reduced after treatment with guanylin- and GC-C-specific siRNAs. Our results suggest that the macrophagic guanylin-GC-C system contributes to the altered expression of genes involved in lipid metabolism, leading to resistance to obesity.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hormonas Gastrointestinales/metabolismo , Macrófagos/metabolismo , Mesenterio/citología , Péptidos Natriuréticos/metabolismo , Receptores Acoplados a la Guanilato-Ciclasa/metabolismo , Receptores de Péptidos/metabolismo , Adipocitos/metabolismo , Animales , Colesterol/sangre , Ácidos Grasos no Esterificados/sangre , Hormonas Gastrointestinales/deficiencia , Hormonas Gastrointestinales/genética , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Insulina/sangre , Hígado/metabolismo , Macrófagos/enzimología , Macrófagos Peritoneales/enzimología , Macrófagos Peritoneales/metabolismo , Masculino , Péptidos Natriuréticos/deficiencia , Péptidos Natriuréticos/genética , Oxidación-Reducción , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Ratas , Ratas Transgénicas , Receptores de Enterotoxina , Receptores Acoplados a la Guanilato-Ciclasa/deficiencia , Receptores Acoplados a la Guanilato-Ciclasa/genética , Receptores de Péptidos/deficiencia , Receptores de Péptidos/genética , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
BACKGROUND: The data on cerebrospinal fluid (CSF) levels of neurotrophins (NTs) in patients with meningoencephalitis are scarce, especially in adult patients. METHODS: We measured CSF levels of NTs such as nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) in adult patients with various meningitis (n = 10) and encephalitis (n = 10) in both acute phase and recovery phase and adult control subjects (n = 21) by the enzyme-linked immunosorbent assay for NTs. RESULTS: Data show that NGF and NT-3 CSF levels were markedly elevated in the patient group in the acute phase compared with non-neurological controls (p < 0.001 and p < 0.05, respectively) and later returned to the levels of controls. Most intriguingly, we only recognized a significant correlation between NGF and NT-3 CSF levels in the patients in the acute phase. CONCLUSION: Such strong correlation of NGF and NT-3 CSF levels strongly suggests that in adult patients, some common regulatory mechanism(s) might be present among various kinds of NTs to cope with central nervous system infection.