Brown rice‐specific γ‐oryzanol as a promising prophylactic avenue to protect against diabetes mellitus and obesity in humans

Abstract Chronic overconsumption of animal fats causes a variety of health problems, including diabetes mellitus and obesity. Underlying molecular mechanisms encompass leptin resistance, a decrease in rewarding effects of physical activities, xanthine oxidase‐induced oxidative stress in vasculature and peripheral tissue, impaired activation of incretin signaling, deviation in food preference, and dysbiosis of gut microbiota. Based on our clinical observation that daily intake of brown rice effectively ameliorates bodyweight gain, impaired glucose tolerance/insulin resistance and dependence on fatty foods in obese, prediabetes men, a line of research on brown rice (rice bran)‐derived γ‐oryzanol in mice experiments, cultured cells and human clinical trials is underway in our laboratory. Our works in mice showed that γ‐oryzanol, an ester mixture of ferulic acid and several kinds of phytosterols, acts as a molecular chaperone, thereby attenuating the strong preference for animal fats through suppression of endoplasmic reticulum stress in the hypothalamus. In pancreatic islets from both high‐fat diet‐induced and streptozotocin‐induced diabetic mice, γ‐oryzanol ameliorates endoplasmic reticulum stress and protects β‐cells against apoptosis. Noticeably, γ‐oryzanol also acts as a potent inhibitor against deoxyribonucleic acid methyltransferases in the brain reward system (striatum) in mice, thereby attenuating, at least partly, the preference for a high‐fat diet through the epigenetic modulation of striatal dopamine D2 receptor. Because dopamine D2 receptor signaling in the brain reward system is considerably attenuated in obese humans and rodents, γ‐oryzanol might represent a unique property to ameliorate both hedonic and metabolic dysregulation of feeding behavior, highlighting a promising prophylactic avenue to protect against metabolic derangement

Effects of High-Fat Diet on the Gut Microbiota of Renalase Gene Knockout Mice

Metabolic diseases caused by gene and unhealthy living habits are increasing, which seriously threaten the life of people worldwide. Moreover, the microbiome has been shown to play an active role in the prevention and treatment of metabolic diseases. However, reliable evidence on renalase gene (Rnls), as a common gene related to metabolic diseases, is still lacking with regard to the influence on the microbiome. Hence, we investigated the effect of a normal diet (ND) and a high-fat diet (HFD) on the gut microbiota of Rnls knockout (Rnls−/−) and wild-type (Rnls+/+) mice. At the end of the 8-week experiment, DNA samples were extracted from fresh feces, and the composition of microbiota was profiled. The species in Rnls+/+-ND group were Bifidobacterium pseudolongum and Lactobacillus reuteri. Conversely, the species in Rnls−/−-ND group belonged to the genera Lactobacillus and Turicibacter. The HFD changed the ratio of Firmicutes/Bacteroidetes; while the bacteria in the Rnls+/+-HFD and Rnls−/−-HFD groups were different. Overall, this study not only revealed the composition of microbiota in Rnls−/− mice, but also indicated that Rnls and the bacteria related to Rnls may be new candidates in the prevention and diagnosis of metabolic diseases at an early stage

Effects of High-Fat Diet on the Gut Microbiota of Renalase Gene Knockout Mice

Metabolic diseases caused by gene and unhealthy living habits are increasing, which seriously threaten the life of people worldwide. Moreover, the microbiome has been shown to play an active role in the prevention and treatment of metabolic diseases. However, reliable evidence on renalase gene (Rnls), as a common gene related to metabolic diseases, is still lacking with regard to the influence on the microbiome. Hence, we investigated the effect of a normal diet (ND) and a high-fat diet (HFD) on the gut microbiota of Rnls knockout (Rnls−/−) and wild-type (Rnls+/+) mice. At the end of the 8-week experiment, DNA samples were extracted from fresh feces, and the composition of microbiota was profiled. The species in Rnls+/+-ND group were Bifidobacterium pseudolongum and Lactobacillus reuteri. Conversely, the species in Rnls−/−-ND group belonged to the genera Lactobacillus and Turicibacter. The HFD changed the ratio of Firmicutes/Bacteroidetes; while the bacteria in the Rnls+/+-HFD and Rnls−/−-HFD groups were different. Overall, this study not only revealed the composition of microbiota in Rnls−/− mice, but also indicated that Rnls and the bacteria related to Rnls may be new candidates in the prevention and diagnosis of metabolic diseases at an early stage

One Week of CDAHFD Induces Steatohepatitis and Mitochondrial Dysfunction with Oxidative Stress in Liver

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increasing worldwide. A choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) has been used to create a mouse model of nonalcoholic steatohepatitis (NASH). There are some reports on the effects on mice of being fed a CDAHFD for long periods of 1 to 3 months. However, the effect of this diet over a short period is unknown. Therefore, we examined the effect of 1-week CDAHFD feeding on the mouse liver. Feeding a CDAHFD diet for only 1-week induced lipid droplet deposition in the liver with increasing activity of liver-derived enzymes in the plasma. On the other hand, it did not induce fibrosis or cirrhosis. Additionally, it was demonstrated that CDAHFD significantly impaired mitochondrial respiration with severe oxidative stress to the liver, which is associated with a decreasing mitochondrial DNA copy number and complex proteins. In the gene expression analysis of the liver, inflammatory and oxidative stress markers were significantly increased by CDAHFD. These results demonstrated that 1 week of feeding CDAHFD to mice induces steatohepatitis with mitochondrial dysfunction and severe oxidative stress, without fibrosis, which can partially mimic the early stage of NASH in humans

Activity of xanthine oxidase in plasma correlates with indices of insulin resistance and liver dysfunction in patients with type 2 diabetes mellitus and metabolic syndrome: A pilot exploratory study

Abstract Aims/Introduction There is controversy as to whether hyperuricemia is an independent risk factor for cardiometabolic diseases. The serum level of uric acid is affected by a wide variety of factors involved in its production and excretion. In contrast, evidence has accumulated that locally‐ and systemically‐activated xanthine oxidase (XO), a rate‐limiting enzyme for production of uric acid, is linked to metabolic derangement in humans and rodents. We therefore explored the clinical implication of plasma XO activity in patients with type 2 diabetes mellitus and metabolic syndrome (MetS). Materials and Methods We enrolled 60 patients with type 2 diabetes mellitus and MetS. MetS was defined according to the 2005 International Diabetes Federation guidelines. Plasma XO activity was measured by highly‐sensitive fluorometric assay measuring the conversion of pterin to isoxanthopterin, and explored associations between the value of plasma XO activity and metabolic parameters. Results The value of plasma XO activity was correlated with indices of insulin resistance and the level of circulating liver transaminases. In contrast, the level of serum uric acid was not correlated with indices of insulin resistance. The value of plasma XO activity was not correlated with the serum uric acid level. Conclusions Plasma XO activity correlates with indices of insulin resistance and liver dysfunction in Japanese patients with type 2 diabetes mellitus and MetS. Through assessing the plasma XO activity, patients showing normal levels of serum uric acid with higher activity of XO can be screened, thereby possibly providing a clue to uncovering metabolic risks in type 2 diabetes mellitus and MetS patients

The International Linear Collider: Report to Snowmass 2021

The International Linear Collider (ILC) is on the table now as a new global energy-frontier accelerator laboratory taking data in the 2030s. The ILC addresses key questions for our current understanding of particle physics. It is based on a proven accelerator technology. Its experiments will challenge the Standard Model of particle physics and will provide a new window to look beyond it. This document brings the story of the ILC up to date, emphasizing its strong physics motivation, its readiness for construction, and the opportunity it presents to the US and the global particle physics community

The International Linear Collider: Report to Snowmass 2021

The International Linear Collider (ILC) is on the table now as a new global energy-frontier accelerator laboratory taking data in the 2030s. The ILC addresses key questions for our current understanding of particle physics. It is based on a proven accelerator technology. Its experiments will challenge the Standard Model of particle physics and will provide a new window to look beyond it. This document brings the story of the ILC up to date, emphasizing its strong physics motivation, its readiness for construction, and the opportunity it presents to the US and the global particle physics community