γ-Oryzanol protects pancreatic ß-cells against endoplasmic reticulum stress in male mice.

Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of ß-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 ß-cells using murine ß-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 ß-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 ß-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

A novel insulinotropic mechanism of whole grain-derived γ-oryzanol via the suppression of local dopamine D2 receptor signalling in mouse islet.

BACKGROUND AND PURPOSE: γ-Oryzanol, derived from unrefined rice, attenuated the preference for dietary fat in mice, by decreasing hypothalamic endoplasmic reticulum stress. However, no peripheral mechanisms, whereby γ-oryzanol could ameliorate glucose dyshomeostasis were explored. Dopamine D2 receptor signalling locally attenuates insulin secretion in pancreatic islets, presumably via decreased levels of intracellular cAMP. We therefore hypothesized that γ-oryzanol would improve high-fat diet (HFD)-induced dysfunction of islets through the suppression of local D2 receptor signalling. EXPERIMENTAL APPROACH: Glucose metabolism and regulation of molecules involved in D2 receptor signalling in pancreatic islets were investigated in male C57BL/6J mice, fed HFD and treated with γ-oryzanol . In isolated murine islets and the beta cell line, MIN6 , the effects of γ-oryzanol on glucose-stimulated insulin secretion (GSIS) was analysed using siRNA for D2 receptors and a variety of compounds which alter D2 receptor signalling. KEY RESULTS: In islets, γ-oryzanol enhanced GSIS via the activation of the cAMP/PKA pathway. Expression of molecules involved in D2 receptor signalling was increased in islets from HFD-fed mice, which were reciprocally decreased by γ-oryzanol. Experiments with siRNA for D2 receptors and D2 receptor ligands in vitro suggest that γ-oryzanol suppressed D2 receptor signalling and augmented GSIS. CONCLUSIONS AND IMPLICATIONS: γ-Oryzanol exhibited unique anti-diabetic properties. The unexpected effects of γ-oryzanol on D2 receptor signalling in islets may provide a novel; natural food-based, approach to anti-diabetic therapy.

Lipid deposition in various sites of the skeletal muscles and liver exhibits a positive correlation with visceral fat accumulation in middle-aged Japanese men with metabolic syndrome.

Objective In addition to excess visceral fat, lipid deposition in the liver and skeletal muscle has been implicated in the pathophysiology of type 2 diabetes and metabolic syndrome. This study was designed to explore the relationship between hepatic and muscular lipid deposition and visceral fat accumulation in 105 middle-aged men with metabolic syndrome. Methods Abdominal computed tomography (CT) was used to simultaneously evaluate the visceral fat area (VFA) and CT Hounsfield unit (HU) values of three different portions of skeletal muscle and the liver. Results A significant inverse correlation was observed between the VFA and the CT HU values of the iliopsoas muscle, back muscle, rectus abdominis muscle and liver. Three types of interventions, i.e., lifestyle modification and treatment with antidiabetic drugs, such as Pioglitazone or Miglitol, caused significant decreases in visceral fat accumulation. The extent of lipid deposition in the liver was strongly correlated with the levels of glucose-lipid metabolic markers, which decreased significantly following Pioglitazone treatment. On the other hand, the amount of lipid deposition in the three skeletal muscles and the liver did not decrease after Miglitol treatment. Conclusion Visceral fat accumulation is accompanied by excess lipid deposition in skeletal muscle and the liver in patients with metabolic syndrome. The CT-based simultaneous, concise evaluations of ectopic lipid deposition and visceral fat mass used in the present study may provide unique information for assessing cardiometabolic risks and the therapeutic impact in patients with diabetes-obesity syndrome.

Brown rice and its component, γ-oryzanol, attenuate the preference for high-fat diet by decreasing hypothalamic endoplasmic reticulum stress in mice.

Brown rice is known to improve glucose intolerance and prevent the onset of diabetes. However, the underlying mechanisms remain obscure. In the current study, we investigated the effect of brown rice and its major component, γ-oryzanol (Orz), on feeding behavior and fuel homeostasis in mice. When mice were allowed free access to a brown rice-containing chow diet (CD) and a high-fat diet (HFD), they significantly preferred CD to HFD. To reduce hypothalamic endoplasmic reticulum (ER) stress on an HFD, mice were administered with 4-phenylbutyric acid, a chemical chaperone, which caused them to prefer the CD. Notably, oral administration of Orz, a mixture of major bioactive components in brown rice, also improved glucose intolerance and attenuated hypothalamic ER stress in mice fed the HFD. In murine primary neuronal cells, Orz attenuated the tunicamycin-induced ER stress. In luciferase reporter assays in human embryonic kidney 293 cells, Orz suppressed the activation of ER stress-responsive cis-acting elements and unfolded protein response element, suggesting that Orz acts as a chemical chaperone in viable cells. Collectively, the current study is the first demonstration that brown rice and Orz improve glucose metabolism, reduce hypothalamic ER stress, and, consequently, attenuate the preference for dietary fat in mice fed an HFD.