Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Abstract

PPARa is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPARa is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPARa ligands on the intracellular calcium concentration ([Ca 2C ] i ), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPARa agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-D. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPARa is present in b-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPARa ligand effects in mice bearing a disrupted Ppara gene raises the possibility that the rapid effects of the agonists in pancreatic b-cells are independent of the receptor. We conclude that PPARa agonists produce a decrease in glucose-induced [Ca 2C ] i signals and insulin secretion in b-cells through a rapid, non-genomic mechanism.

Complex role of peroxisome proliferator activator receptors (PPARs) in nociception

“…PPRE is highly conserved in different species, suggesting a fundamental role for the pathways it activates in a variety of fundamental biological processes. In addition to these genomic effects, receptor-like almost instantaneous responses (within minutes), independent of gene activation have also been described (reviewed in [7]), consistent with the earlier finding that a fraction of the PPAR␣ proteins is located at the cell DOI membrane [8]. This novel observation added even more complexity to the previous canonical vision on genomic PPAR signalling.…”

“…The authors show that intraperitoneal administration of the synthetic PPAR␣ agonist WY-14643 attenuated key symptoms of neuropathic pain in rats. The authors also obtained original data suggesting, unlike previous views on the peripheral role of PPAR␣ [8], the involvement of spinal neurons in nociceptive signal processing in spinal nerve ligation model of neuropathic pain. The principal significance of the latter relies on the rationale route of drug administrations to counteract spinally located neuropathic pain.…”

Proliferation and fission of peroxisomes — An update

“…Other possible activation pathways for PPARα include the involvement of protein kinase cascades, including Src [172], p38 [153,160], ERK1/2 [21,193], MEK1 [193], Ras [50], and EGFR [50]. Moreover, GW7647 and other PPARα agonists affect calcium signalling in various cell types, including pancreatic β-cells [132] and eosinophils [153]. Finally, a GW7647-induced PPARα-binding region has also been assigned to Sterol regulatory elementbinding protein (SREBP)-targets HMGCS1, HMGCR and LPIN1, suggesting cross-talk between PPARα and SREBP signalling [1].…”

Alteration of neuropathic and visceral pain in female C57BL/6J mice lacking the PPAR-α gene

“…Logically, other mechanisms apart from inflammation could be involved. In this context, modulation of PPAR-α with ligands has demonstrated to produce rapid non-genomic responses including satiety, calcium responses in secretory cells, and modifications of gastrointestinal motility (Ahern 2003;Su et al 2006;Ropero et al 2009;Cluny et al 2009). These findings indicate that PPAR-α may engage additional signaling mechanisms that are not related to genomic regulation of inflammation, and these mechanisms may contribute to the responses observed.…”