A novel insulinotropic mechanism of whole grain-derived -oryzanol via the suppression of local dopamine D-2 receptor signalling in mouse islet

作者：Kozuka Chisayo; Sunagawa Sumito; Ueda Rei; Higa Moritake; Ohshiro Yuzuru; Tanaka Hideaki; Shimizu Okabe Chigusa; Takayama Chitoshi; Matsushita Masayuki; Tsutsui Masato; Ishiuchi Shogo; Nakata Masanori; Yada Toshihiko; Miyazaki Jun ichi; Oyadomari Seiichi; Shimabukuro Michio; Masuzaki Hiroaki^*

来源：British Journal of Pharmacology, 2015, 172(18): 4519-4534.

DOI：10.1111/bph.13236

Background and Purpose
gamma-Oryzanol, derived from unrefined rice, attenuated the preference for dietary fat in mice, by decreasing hypothalamic endoplasmic reticulum stress. However, no peripheral mechanisms, whereby -oryzanol could ameliorate glucose dyshomeostasis were explored. Dopamine D-2 receptor signalling locally attenuates insulin secretion in pancreatic islets, presumably via decreased levels of intracellular cAMP. We therefore hypothesized that -oryzanol would improve high-fat diet (HFD)-induced dysfunction of islets through the suppression of local D-2 receptor signalling.
Experimental Approach
Glucose metabolism and regulation of molecules involved in D-2 receptor signalling in pancreatic islets were investigated in male C57BL/6J mice, fed HFD and treated with gamma-oryzanol . In isolated murine islets and the beta cell line, MIN6 , the effects of gamma-oryzanol on glucose-stimulated insulin secretion (GSIS) was analysed using siRNA for D-2 receptors and a variety of compounds which alter D-2 receptor signalling.
Key Results
In islets, -oryzanol enhanced GSIS via the activation of the cAMP/PKA pathway. Expression of molecules involved in D-2 receptor signalling was increased in islets from HFD-fed mice, which were reciprocally decreased by -oryzanol. Experiments with siRNA for D-2 receptors and D-2 receptor ligands in vitro suggest that gamma-oryzanol suppressed D-2 receptor signalling and augmented GSIS.
Conclusions and Implications
gamma-Oryzanol exhibited unique anti-diabetic properties. The unexpected effects of gamma-oryzanol on D-2 receptor signalling in islets may provide a novel; natural food-based, approach to anti-diabetic therapy.

• 出版日期2015-9