MON-201 Effects of Incretins on Catecholamine Synthesis by Rat Pheochromocytoma PC12 Cells

Incretins, such as gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are metabolic hormones secreted from the intestine to stimulate insulin secretion from the pancreatic β cells. Dipeptidyl peptidase-4 (DPP-4) inhibitors, as anti-diabetic agents, increase the bioavailability of both GIP and GLP-1. Since the receptor expressions of GIP and GLP-1 are detected in various organs, incretins have been suggested to affect many kinds of tissues and organs in addition to their insulinotropic effects. For instance, GIP and GLP-1 have been reported to regulate ovarian steroidogenesis and hypothalamic-pituitary-adrenal axis including secretions of adrenocorticotropin from the pituitary and cortisol from the adrenal cortex. However, the roles of GIP and GLP-1 in the adrenal medulla have not been recognized. Here we focused on the activity of bone morphogenetic protein (BMP)-4, which is expressed in the adrenal medulla and is functionally involved in the control of catecholamine synthesis. We earlier reported that BMP-4 treatment decreased catecholamine synthesis via smad1/5/9 phosphorylation and regulated catecholamine synthesis by cooperating with glucocorticoid and melatonin in rat pheochromocytoma PC12 cells. In the present study, roles of GIP and GLP-1 in the regulation of catecholamine production were studied using PC12 cells by focusing on interaction with BMP-4 and adrenocortical steroids. Both of GIP receptor and GLP-1 receptor expressions were detected in PC12 cells. Of note, treatments with GIP, but not with GLP-1, increased dopamine synthesis and the mRNA levels of catecholamine synthetic enzymes including tyrosine hydroxylase (TH), which is a rate-limiting enzyme for catecholamine synthesis, DOPA decarboxylase (DDC), and dopamine β-hydroxylase (DBH), by PC12 cells. Treatments with GIP enhanced glucocorticoid- and aldosterone-induced TH mRNA levels by upregulating the expressions of glucocorticoid receptor (GR) as well as mineralocorticoid receptor (MR). However, treatment with GLP-1 had no effect on corticosteroid-induced TH mRNA levels or GR/MR expression. On the other hand, treatment with GIP attenuated the inhibitory effect of BMP-4 that enables to decrease TH mRNA levels by suppressing BMP-induced Smad1/5/9 phosphorylation and Id-1 transcription. Furthermore, GIP treatment upregulated the expression of inhibitory Smad7, possibly leading to the suppression of BMP-4 signaling by PC12 cells. Collectively, it was revealed that incretins, in particular, GIP has an inducing effect on catecholamine synthesis through inhibiting BMP activities as well as enhancing corticosteroid actions in adrenomedullar cells.