RESUMO
Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.
Assuntos
Metabolismo Energético , Hipotálamo/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Transdução de Sinais , Hormônios Tireóideos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Termogênese , Tri-Iodotironina/metabolismoRESUMO
SCOPE: To determine whether the insulin resistance that exists in metabolic syndrome (MetS) patients is modulated by dietary fat composition. METHODS AND RESULTS: Seventy-five patients were randomly assigned to one of four diets for 12 wk: high-saturated fatty acids (HSFAs), high-MUFA (HMUFA), and two low-fat, high-complex carbohydrate (LFHCC) diets supplemented with long-chain n-3 (LFHCC n-3) PUFA or placebo. At the end of intervention, the LFHCC n-3 diet reduced plasma insulin, homeostasis model assessment of insulin resistance, and nonsterified fatty acid concentration (p < 0.05) as compared to baseline Spanish habitual (BSH) diet. Subcutaneous white adipose tissue (WAT) analysis revealed decreased EH-domain containing-2 mRNA levels and increased cbl-associated protein gene expression with the LFHCC n-3 compared to HSFA and HMUFA diets, respectively (p < 0.05). Moreover, the LFHCC n-3 decreased gene expression of glyceraldehyde-3-phosphate dehydrogenase with respect to HMUFA and BSH diets (p < 0.05). Finally, proteomic characterization of subcutaneous WAT identified three proteins of glucose metabolism downregulated by the LFHCC n-3 diet, including annexin A2. RT-PCR analysis confirmed the decrease of annexin A2 (p = 0.027) after this diet. CONCLUSION: Our data suggest that the LFHCC n-3 diet reduces systemic insulin resistance and improves insulin signaling in subcutaneous WAT of MetS patients compared to HSFA and BSH diets consumption.
Assuntos
Tecido Adiposo Branco/metabolismo , Dieta , Gorduras na Dieta/administração & dosagem , Resistência à Insulina , Síndrome Metabólica/metabolismo , Gordura Subcutânea/metabolismo , Anexina A2/genética , Anexina A2/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Carboidratos da Dieta/administração & dosagem , Ácidos Graxos Monoinsaturados , Ácidos Graxos Insaturados/administração & dosagem , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Insulina/sangue , Estilo de Vida , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Previously, it has been shown that background color conditions regulate the overall activity of the frog intermediate lobe by varying the proportions of the two subtypes of melanotropes existing in the gland, the highly active or secretory melanotropes and hormone storage melanotropes, depending on melanocyte-stimulating hormone requirements. However, the factors and mechanisms underlying these background-induced changes are still unknown. In the present study, we investigated whether hypothalamic factors known to regulate melanotrope cell function can induce changes in vitro similar to those caused by background adaptation in vivo. We found that the inhibitors apomorphine (a dopamine receptor agonist) and neuropeptide Y decreased the number of active melanotropes and increased simultaneously that of storage melanotropes. On the other hand, the stimulator TRH increased the number of active cells and concomitantly reduced that of storage cells. Inasmuch as none of these treatments modified the apoptotic and proliferation rates in melanotrope cells, it appears that these hypothalamic factors caused actual interconversions of cells from a subpopulation to its counterpart. Taken together, these findings suggest that the hypothalamus would control melanotrope activity not only through short-term regulation of hormone synthesis and release, but also through a long-term regulation of the secretory phenotype of these cells whereby the activity of the intermediate lobe would be adjusted to fulfill the hormonal requirements imposed by background conditions.