Both
peroxisome proliferator-activated receptor-alpha (
PPARalpha) and pancreatic/duodenal homeobox-1 (PDX-1) have been reported to be associated with
glucose-stimulated insulin secretion (GSIS), but the relationship between
PPARalpha and PDX-1 is not yet fully understood. In the present study, we tested the hypothesis that
PPARalpha regulates the expression of PDX-1 in beta-cells. Isolated pancreatic islets from Wistar rats and rat pancreatic
insulinoma (INS-1) beta-cells were cultured in media supplemented with and without 0.2 or 0.4 mm
palmitate, and treated with and without a
PPARalpha agonist (
fenofibrate) or
PPARalpha antagonist (
MK886). Results indicated that treatment with
fenofibrate significantly enhanced
PPARalpha mRNA and
protein expression in cells cultured with elevated
palmitate concentrations compared with cells that did not receive
fenofibrate treatment. In turn, this enhanced expression led to an increase in PDX-1
mRNA and
nuclear protein, as well as
DNA binding activity of PDX-1 with the
insulin promoter. Accordingly, the expression of the PDX-1 downstream targets,
insulin and
glucose transporter-2, increased, resulting in increased intracellular
insulin content and GSIS. Treatment with
MK886 inhibited expression of
PPARalpha, blocking
PPARalpha-regulated PDX-1 expression, and the downstream transcription events of PDX-1. EMSA revealed that
nuclear protein might bind with the peroxisome proliferator response element sequence located in the PDX-1 promoter. Collectively, these results demonstrate a regulatory relationship between
PPARalpha and PDX-1 in INS-1 cells. Furthermore,
PPARalpha activation potentiates GSIS under elevated
palmitate conditions possibly via up-regulation of PDX-1. Our findings have potential clinical implications for the use of
PPARalpha agonists in the treatment of
type 2 diabetes.