RESUMO
Palmitic acid (PA) is a saturated fatty acid whose high consumption has been largely associated with the development of different metabolic alterations, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Particularly in the brain, insulin signaling disruption has been linked to cognitive decline and is considered a risk factor for Alzheimer's disease. Cumulative evidence has demonstrated the participation of PA in the molecular cascade underlying cellular insulin resistance in peripheral tissues, but its role in the development of neuronal insulin resistance and the mechanisms involved are not fully understood. It has generally been accepted that the brain does not utilize fatty acids as a primary energy source, but recent evidence shows that neurons possess the machinery for fatty acid ß-oxidation. However, it is still unclear under what conditions neurons use fatty acids as energy substrates and the implications of their oxidative metabolism in modifying insulin-stimulated effects. In the present work, we have found that neurons differentiated from human neuroblastoma MSN exposed to high but nontoxic concentrations of PA generate ATP through mitochondrial metabolism, which is associated with an increase in the cytosolic Ca2+ and diminished insulin signaling in neurons. These findings reveal a novel mechanism by which saturated fatty acids produce Ca2+ entry and insulin resistance that may play a causal role in increasing neuronal vulnerability associated with metabolic diseases.
Assuntos
Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Resistência à Insulina/fisiologia , Neurônios/efeitos dos fármacos , Ácido Palmítico/farmacologia , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Citosol/efeitos dos fármacos , Citosol/metabolismo , Ácidos Graxos/farmacologia , Humanos , Insulina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neuroblastoma/metabolismo , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Store-operated calcium entry (SOCE) is an essential calcium influx mechanism in animal cells. One of the most important auto regulatory control systems involves calcium-dependent inactivation (CDI) of the Orai channel, which prevents excessive calcium influx. In the present study we analyze the role of two channels in the induction of CDI on Orai1. Here we show that calcium entering through freely diffusing TRPV1 channels induce strong CDI on Orai1 while calcium entering through P2X4 channel does not. TRPV1 can induce CDI on Orai1 because both channels were found in close proximity in the cell membrane. This was not observed with P2X4 channels. To our knowledge, this is the first study demonstrating that calcium arising from different channels may contribute to the modulation of Orai1 through CDI in freely diffusing single channels of living cells. Our results highlight the role of TRPV1-mediated CDI on Orai1 in cell migration and wound healing.