Leptin signalling in pancreatic islets and clonal insulin-secreting cells

Abstract

Leptin is a cytokine secreted from adipose tissue at a rate commensurate with the size of the body's fat stores. In addition to its anorectic and thermogenic central actions, leptin is known to act on peripheral tissues, including the pancreatic -cell where it inhibits insulin secretion and reduces insulin transcript levels. However, the role of leptin signalling through its full-length receptor, OB-Rb, in the -cell remains unclear. In the present study, we show that leptin activates a signal transducer and activator of transcription (STAT)3 signalling mechanism in pancreatic islets and in a rat model of the pancreatic -cell, RINm5F. Leptin induced DNA binding to a STAT consensus oligonucleotide and resulted in transcriptional activation from STAT reporter constructs in a manner consistent with STAT3 activation. Western blot analysis confirmed activation of STAT3 in RINm5F and isolated rat islets. Conditions that mimic increased metabolic activity resulted in attenuation of leptin-mediated STAT DNA binding but had no significant effect on STAT3 tyrosine phosphorylation in RINm5F cells. In addition, leptin activated the mitogen activated protein (MAP) kinase pathway in RINm5F cells. The present study provides a framework for OB-Rb signalling mechanisms in the programming of the -cell by leptin and suggests that increased metabolic activity may modulate this function.

Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period

“…db/db Mice display obesity and type 2 diabetes, due to the absence of functional leptin receptors, the main activator of STAT3 in pancreatic b-cells (Shafrir 1992, Morton et al 1999. We have demonstrated that adult pancreatic islets, cultured with PRL, show an upregulation in STAT3 gene expression .…”

LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

“…Leptin and its receptors signaling is transducted through multiple pathways, including PI3K (37), JAK-STAT3 and ERK pathways (9). To determine the downstream signaling of leptin affecting Isl-1 expression and insulin secretion, NIT cells were treated with 10 ng/ml leptin for 0, 5, 10, 20, and 30 min, and the phosphorylated STAT3 and phosphorylated ERK were analyzed by Western blot.…”

“…Leptin also lowers the intracellular free calcium concentration ([Ca 2ϩ ] i ) of pancreatic beta cells (4). In addition, leptin has been shown to act through its full-length receptor (OBRb) 4 and activate the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway in pancreatic islets (9). The activation of OBRb induces JAK-STAT3, which is implicated in transcriptional modulation (10).…”

Regulation of insulin gene transcription

“…Although STAT5 b has been shown to activate the rat I promoter through the same STAT5 motif in response to growth hormone, it is likely that leptin mediates the repression through multiple additional complexes detected in this region. Leptin activated the STAT3 pathway by increasing the phosphorylation of STAT3 and MAP Kinase pathway in RINm5F cells [174]. Thus, the importance of JAK/STAT and possibly MAP Kinase signalling pathways in the regulation of insulin gene expression by leptin is not clear.…”