Abstract
BackgroundLeptin acts not only on hypothalamic centers to control food intake but has additional functions in peripheral tissues, e.g. inhibition of insulin secretion from pancreatic islets. The leptin receptor (LEPRb) is a class I cytokine receptor that mediates activation of STAT transcription factors. In this study, we characterise the regulation of inflammation-related genes by leptin in insulinoma cells and compare the effect of transcriptional regulation by leptin with that of other cytokines.ResultsWe have used RINm5F insulinoma cells as a model system for a peripheral target cell of leptin. Six transcripts encoding inflammation-related proteins were found to be upregulated by activation of LEPRb, namely lipocalin-2, pancreatitis-associated protein, preprotachykinin-1, fibrinogen-β, tissue-type plasminogen activator (tPA) and manganese-dependent superoxide dismutase (MnSOD). Four of these transcripts (fibrinogen-β, lipocalin-2, tPA, MnSOD) were also induced by the proinflammatory cytokine interleukin-1β (IL-1β). Interferon-γ alone had no effect on the leptin-induced transcripts but enhanced the upregulation by IL-1β of lipocalin-2, tPA and MnSOD mRNA levels. Experiments with LEPRb point mutants revealed that the upregulation of the inflammation-related genes depended on the presence of tyrosine-1138 which mediates the activation of the transcription factors STAT1 and STAT3. Reporter gene assays showed that leptin induced the expression of preprotachykinin-1 and lipocalin-2 on the level of promoter regulation. Finally, leptin treatment increased caspase 3-like proteolytic activity in RINm5F cells.ConclusionThe present data show that leptin induces a cytokine-like transcriptional response in RINm5F cells, consistent with the proposed function of leptin as a modulator of immune and inflammatory responses.
Highlights
Leptin acts on hypothalamic centers to control food intake but has additional functions in peripheral tissues, e.g. inhibition of insulin secretion from pancreatic islets
Six transcripts encoding inflammation-related proteins were found to be upregulated by activation of LEPRb, namely lipocalin-2, pancreatitis-associated protein, preprotachykinin-1, fibrinogen-β, tissue-type plasminogen activator and manganese-dependent superoxide dismutase (MnSOD)
Experiments with LEPRb point mutants revealed that the upregulation of the inflammation-related genes depended on the presence of tyrosine-1138 which mediates the activation of the transcription factors STAT1 and STAT3
Summary
Leptin acts on hypothalamic centers to control food intake but has additional functions in peripheral tissues, e.g. inhibition of insulin secretion from pancreatic islets. Leptin is a cytokine which is secreted predominantly by white adipose tissue and exerts its effects on appetite and thermogenesis on centers located in the hypothalamus [1] In addition to these well defined central actions, it has become clear that leptin has important peripheral effects, including the regulation of the immune system and the modulation of insulin secretion from the pancreas [2,3,4]. Leptin activates ATP-sensitive K+ channels on β-cells and thereby antagonises depolarisation required for insulin secretion [9] These are both unusual pathways, considering that the leptin receptor (LEPR) belongs to the class I cytokine receptor family and transmits signals mainly via the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway [10]. STAT factors are well known to regulate transcription, the range of transcriptional targets responsive to leptin stimulation of pancreatic β-cells is not well characterised [19]
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