γ-Oryzanol Protects Pancreatic β-Cells Against Endoplasmic Reticulum Stress in Male Mice

Abstract

Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

Marked augmentation of PLGA nanoparticle-induced metabolically beneficial impact of γ-oryzanol on fuel dyshomeostasis in genetically obese-diabetic ob/ob mice

“…Although g-oryzanol has a wide variety of beneficially metabolic effects (Kozuka et al, 2012;Kozuka et al, 2013;Kozuka et al, 2015a, Kozuka et al, 2015b, extremely low absorption efficiency from intestine of g-oryzanol is a tough obstacle for the clinical application. Gamma-oryzanol ameliorates preference for animal fat and fuel metabolism in HFD-fed mice (Kozuka et al, 2012(Kozuka et al, , 2013(Kozuka et al, , 2015a(Kozuka et al, , 2015b. However, in ob/ob mice, the bestknown severest diabetic model in mice, g-oryzanol actually shows no apparent effect on metabolic amelioration.…”

“…In pancreatic islets from both high fat diet (HFD)-induced and streptozotocin-induced diabetic mice, we also demonstrated that g-oryzanol ameliorates ER stress and protects b-cells against apoptosis (Kozuka et al, 2015b). ER stress plays an important role in the pathophysiology of obesity-diabetes syndrome in a variety of tissues (Hotamisligil, 2010).…”

Disulfide Mispairing During Proinsulin Folding in the Endoplasmic Reticulum

“…In recent years, reports have surfaced regarding pharmacological approaches to correcting misfolding of a subfraction of proteins in the secretory pathway, including mutant enzymes, receptors, transporters, and ion channels (38), such as the cystic fibrosis transmembrane regulator (39), ATP-binding cassette transporters (40), gonadotropin-releasing hormone receptor (41), superoxide dismutase 1 (42), lysosomal enzymes like β-glucosidase (43), and others. Pharmacotherapies are beginning to be reported that can ameliorate ER stress in pancreatic β-cells as well (44–47); however, no pharmacotherapies that specifically help correct proinsulin misfolding in the ER have yet been reported. In part, this may be attributed to our still-limited understanding of proinsulin misfolding in the ER context.…”

Antioxidant Activity of γ-Oryzanol: A Complex Network of Interactions

“…However, the development of stress in this organelle is accomplished by several metabolic disorders, resulting from misfolded protein accumulation and ROS formation. Although the organ-specific action of Orz in the pancreas is still unclear, following oral administration, Orz reaches its maximum plasma concentration in about 1 h. The distribution of Orz occurs mainly in the brain, whereas considerable amounts are found in the pancreas [44]. In the pancreas, Orz has been shown to decrease the expression of ER stress-responsive genes such as Ddit3 (CCAAT/enhancer-binding protein-homologous protein), Dnajb9 (ER resident DNAJ 4), and the spliced form of X box binding protein 1 ( Xbp1s ) [44].…”

“…These results suggest that Orz prevents ER stress-induce apoptosis, and it consequently enhances β-cell insulin production. Although Orz absorption by adipose tissues is lower than in the pancreas [44], it might improve adiponectin levels as discussed earlier. As Orz exerts its effects in the pancreas (it decreases ER stress and improves insulin secretion) and in adipose tissue (it improves adiponectin levels), it is feasible that Orz may display synergic effects in different organs, particularity as they relate to glucose metabolism (Figure 2).…”