RESUMO
OBJECTIVE: Free fatty acids (FFAs) are increased in visceral fat and contribute to insulin resistance through multiple mechanisms, including c-Jun N-terminal kinase (JNK) activation and expression of TNFα. Given that insulin-like growth factor-1 (IGF-1)-mediated proliferation is impaired in omental compared to subcutaneous (SC) preadipocytes, we investigated IGF-I anti-inflammatory action in preadipocytes from SC and omental adipose tissue. DESIGN AND METHODS: Preadipocytes isolated from abdominal SC and omental fat of obese subjects were studied in primary culture. Cells were exposed to FFAs with or without IGF-I pretreatment followed by analysis of cytokine expression and JNK phosphorylation. Lentivirus infection was used to express a constitutively active AKT (myr-AKT) in omental preadipocytes. RESULTS: FFAs increased the expression of tumor necrosis factor (TNF)α, interleukin (IL)-6, and monocyte chemotactic protein (MCP)-1 in SC and omental preadipocytes. IGF-I pretreatment reduced FFA-induced JNK1 phosphorylation and TNFα expression in SC but not omental preadipocytes. Treatment with the JNK1/2 inhibitor SP600125 reduced FFA-induced expression of TNFα. FFAs and MALP-2, a specific TLR2/6 ligand, but not specific ligands for TLR4 and TLR1/2, increased JNK1 phosphorylation. IGF-I completely inhibited MALP-2-stimulated phosphorylation of JNK1. Expression of myr-AKT in omental preadipocytes inhibited FFA-stimulated JNK1 phosphorylation. CONCLUSIONS: IGF-I attenuated FFA-induced JNK1 phosphorylation and TNFα expression through activation of AKT in human subcutaneous but not omental preadipocytes.
Assuntos
Adipócitos/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Gordura Intra-Abdominal/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Gordura Subcutânea Abdominal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adipócitos/efeitos dos fármacos , Adulto , Antracenos/farmacologia , Distribuição da Gordura Corporal , Ácidos Graxos não Esterificados/farmacologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Fator de Crescimento Insulin-Like I/farmacologia , Gordura Intra-Abdominal/efeitos dos fármacos , Lipopeptídeos/metabolismo , Masculino , Obesidade/metabolismo , Omento , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Gordura Subcutânea Abdominal/efeitos dos fármacos , Receptores Toll-Like/metabolismoRESUMO
Inhaled corticosteroids (ICS) are drugs of choice for persistent asthma. Less than 500 µg/d of fluticasone are believed to be safe. We found 92 cases of adrenal suppression in PubMed; among these cases there were 13 children who took 500 µg/d or less of fluticasone. Adrenal insufficiency was diagnosed in a 7-year-old boy on 460 µg ICS for 16 months, with a diagnosis of chronic persistent asthma. A random cortisol was nondetectable as was an early morning cortisol. ICS have greatly improved the day-to-day lives of children with chronic persistent asthma. Parents of children younger than 12 years, who use at least 400 µg of inhaled fluticasone (or bioequivalent), must be given oral and written instructions about warning symptoms of hypocortisolism. Major stress such as surgery, gastrointestinal, bronchopulmonary, or other systemic infections, and heat stress may mandate a written plan of action for use by hospital physicians.
