Abstract
Leptin, an adipocyte-derived hormone, centrally regulates energy homeostasis. Overlaps in the regulation of glucose and energy homeostasis have been reported between leptin and insulin. However, the effects of insulin on leptin’s actions in the central nervous system (CNS) have not yet been elucidated in detail. In the present study, we found that insulin potentiated leptin’s actions through GRP78 in the neuronal cell line, SH-SY5Y-ObRb. Since insulin induces GRP78, we speculated that it may also enhance leptin’s actions through this induction. We found that insulin enhanced leptin-induced STAT3 phosphorylation and this effect was ameliorated by the knockdown of GRP78. The role of GRP78 in leptin’s actions was also confirmed by impairments in leptin-induced STAT3 phosphorylation in HEK293-ObRb cells in which GRP78 was knocked down. Furthermore, we found that the overexpression of GRP78 enhanced leptin-induced STAT3 phosphorylation. These results suggest that GRP78 plays an important role in leptin’s actions. Furthermore, insulin may enhance the leptin-induced activation of STAT3 by inducing GRP78, which may provide an important connection between insulin and leptin in the CNS.
Highlights
Leptin, an adipocyte-derived hormone, centrally regulates energy homeostasis
PI3K and mammalian target of rapamycin activities are necessary for insulin-induced metabolic pathways[29,30]
Insulin failed to enhance leptin-induced STAT3 activation in Glucose-regulated protein 78 (GRP78)-knocked down cells (Fig. 4). These results suggest that insulin enhances leptin-induced STAT3 phosphorylation via the induction of GRP78
Summary
An adipocyte-derived hormone, centrally regulates energy homeostasis. Overlaps in the regulation of glucose and energy homeostasis have been reported between leptin and insulin. We found that the overexpression of GRP78 enhanced leptin-induced STAT3 phosphorylation These results suggest that GRP78 plays an important role in leptin’s actions. The neuronal response to leptin receptor activation is mediated through the Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) cascade[4,5,6] It currently remains unknown whether leptin is the only hormone involved in the control of energy balance. The pancreatic hormone, insulin, mediates the hypothalamic regulation of energy homeostasis and glucose metabolism[7,8]. Induction of GRP78 by insulin[28] and its critical role in response to ER stress, the aim of the present study was to investigate the function of GRP78 in leptin signaling in insulin-treated neuronal cells
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