Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
Am J Physiol Endocrinol Metab ; 315(2): E267-E278, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29634311

RESUMO

Skeletal muscle is the major site of postprandial peripheral glucose uptake, but in obesity-induced insulin-resistant states insulin-stimulated glucose disposal is markedly impaired. Despite the importance of skeletal muscle in regulating glucose homeostasis, the specific transcriptional changes associated with insulin-sensitive vs. -resistant states in muscle remain to be fully elucidated. Herein, using an RNA-seq approach we identified 20 genes differentially expressed in an insulin-resistant state in skeletal muscle, including cysteine- and glycine-rich protein 3 ( Csrp3), which was highly expressed in insulin-sensitive conditions but significantly reduced in the insulin-resistant state. CSRP3 has diverse functional roles including transcriptional regulation, signal transduction, and cytoskeletal organization, but its role in glucose homeostasis has yet to be explored. Thus, we investigated the role of CSRP3 in the development of obesity-induced insulin resistance in vivo. High-fat diet-fed CSRP3 knockout (KO) mice developed impaired glucose tolerance and insulin resistance as well as increased inflammation in skeletal muscle compared with wild-type (WT) mice. CSRP3-KO mice had significantly impaired insulin signaling, decreased GLUT4 translocation to the plasma membrane, and enhanced levels of phospho-PKCα in muscle, which all contributed to reduced insulin-stimulated glucose disposal in muscle in HFD-fed KO mice compared with WT mice. CSRP3 is a highly inducible protein and its expression is acutely increased after fasting. After 24h fasting, glucose tolerance was significantly improved in WT mice, but this effect was blunted in CSRP3-KO mice. In summary, we identify a novel role for Csrp3 expression in skeletal muscle in the development of obesity-induced insulin resistance.


Assuntos
Glucose/metabolismo , Homeostase/fisiologia , Proteínas com Domínio LIM/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Animais , Dieta Hiperlipídica , Transportador de Glucose Tipo 4/biossíntese , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Proteína Quinase C/metabolismo
2.
Nat Commun ; 9(1): 5272, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30532051

RESUMO

Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Ingestão de Alimentos/genética , Hiperfagia/genética , Animais , Antipsicóticos/toxicidade , Fator de Ligação a CCAAT/genética , Quimioterapia Adjuvante , Proteínas de Ligação a DNA/genética , Ingestão de Alimentos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Hiperfagia/induzido quimicamente , Hiperfagia/tratamento farmacológico , Hipotálamo/metabolismo , Camundongos , Fenótipo , Fatores de Transcrição/genética , Vemurafenib/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA