Disrupting Osr1 expression promoted hepatic steatosis and inflammation induced by high-fat diet in the mouse model.

NAFLD, regarded as the hepatic manifestation of metabolic syndrome, is the most common form of liver disease in the United States. The Odd-skipped related 1 (Osr1) gene was previously reported to play a critical role in embryonic development and as a cancer repressor gene, however its role in overnutrition induced fatty liver disease has never been explored. Induced by a high-fat diet (HFD) for 10-week, the development and the progression of NAFLD was evaluated in either Osr1 heterozygote (Osr1 group) or wildtype mice (WT group). The Osr1 mice, regardless of sex, exhibited more severe steatosis compared to WT. Upregulation of lipogenesis protein including Srebp1c was detected in the Osr1 group, together with impaired IRS2 expression and overactivated Akt/mTOR signaling. In addition, the Osr1 mice had decreased bile acid synthesis in the liver with depressed hepatic expression of Cyp7a1 and Cyp27a1. Furthermore, there was more macrophage infiltration with enhanced expression of Il-1ß and TNF-α in the Osr1 liver, associated with overactivation of JNK and NF-κB signaling. In summary, our study showed that Osr1 plays an important role in regulating the lipid homeostasis and hepatic inflammation, whose disruption contributes to NAFLD progression.

Celastrol alleviates metabolic disturbance in high-fat diet-induced obese mice through increasing energy expenditure by ameliorating metabolic inflammation.

Celastrol, a natural triterpene, has been shown to treat obesity and its related metabolic disorders. In this study, we first assessed the relationship between the antiobesity effects of celastrol and its antiinflammatory activities. Our results showed that celastrol can reduce weight gain, ameliorate glucose intolerance, insulin resistance, and dyslipidemia without affecting food intake in high-fat diet-induced obese mice. A CLAMS was used to clarify the improvement of metabolic profiles was attribute to increased adipose thermogenesis after celastrol treatment. Further studies found that celastrol decreased the infiltration of macrophage as well as its inflammatory products (IL-1ß, IL-18, MCP-1α, and TNF-α) in liver and adipose tissues, which also displayed an obvious inhibition of TLR3/NLRP3 inflammasome molecules. This study demonstrated that celastrol could be a potential drug for treating metabolic disorders, the underlying mechanism is related to ameliorating metabolic inflammation, thus increasing body energy expenditure.

Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease.

Odd-skipped related 1 (Osr1) is a novel tumor suppressor gene in several cancer cell lines. Non-alcoholic steatohepatitis (NASH) is considered as a high-risk factor for hepatocellular carcinoma (HCC). This study is aimed to investigate the novel role of Osr1 in promoting the progression of hepatic steatosis to NASH. Following 12 weeks of diethylnitrosamine (DEN) and high-fat diet (HFD), wildtype (WT) and Osr1 heterozygous (Osr1+/-) male mice were examined for liver injuries. Osr1+/- mice displayed worsen liver injury with higher serum alanine aminotransferase levels than the WT mice. The Osr1+/- mice also revealed early signs of collagen deposition with increased hepatic Tgfb and Fn1 expression. There was overactivation of both JNK and NF-κB signaling in the Osr1+/- liver, along with accumulation of F4/80+ cells and enhanced hepatic expression of Il-1b and Il-6. Moreover, the Osr1+/- liver displayed hyperphosphorylation of AKT/mTOR signaling, associated with overexpression of Bcl-2. In addition, Osr1+/- and WT mice displayed differences in the DNA methylome of the liver cells. Specifically, Osr1-responsible CpG islands of Ccl3 and Pcgf2, genes for inflammation and macrophage infiltration, were further identified. Taken together, Osr1 plays an important role in regulating cell inflammation and survival through multiple signaling pathways and DNA methylation modification for NAFLD progression.

Pregestational diet transition to normal-fat diet avoids the deterioration of pancreatic ß-cell function in male offspring induced by maternal high-fat diet.

Novel progress has been made to understand the adverse pathophysiology in the pancreas of offspring exposed to overnutrition in utero. Our study is the first to evaluate whether the adverse effects of maternal overnutrition on offspring ß-cell function are reversible or preventable through preconception maternal diet interventions. Herein, offspring mice were exposed in utero to one of the following: maternal normal-fat diet (NF group), maternal high-fat diet (HF group) or maternal diet transition from an HF to NF diet 9 weeks before pregnancy (H9N group). Offspring mice were subjected to postweaning HF diet for 12 weeks. HF offspring, but not H9N, displayed glucose intolerance and insulin resistance. HF male offspring had enlarged islet ß-cells with reduced ß-cell density, whereas, H9N male offspring did not show these changes. Co-immunofluorescent (Co-IF) staining of glucose transporter 2 (Glut2) and insulin (Ins) revealed significantly more Glut2+Ins- cells, indicative of insulin degranulation, in HF male offspring but not H9N. In addition, Co-IF of insulin and p-H3S10 indicated that ß cells of HF male offspring, but not H9N, had proliferation defects likely due to inhibited protein kinase B (AKT) phosphorylation. In summary, our study demonstrates that maternal H9N diet effectively prevents functional deterioration of ß cells seen in HF male offspring by avoiding ß-cell proliferation defects and degranulation.

Maternal diet intervention before pregnancy primes offspring lipid metabolism in liver.

Nonalcoholic fatty liver disease (NAFLD) has a developmental origin and is influenced in utero. We aimed to evaluate if maternal diet intervention before pregnancy would be beneficial to reduce the risk of offspring NAFLD. In our study, female mice were either on a normal-fat diet (NF group), or a high-fat diet for 12 weeks and continued on this diet throughout pregnancy and lactation (HF group), or switched from HF-to-NF diet 1 week (H1N group), or 9 weeks (H9N group) before pregnancy. Compared with the NF offspring, the H1N and HF, but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, an abnormal blood lipid panel was seen in the H1N offspring and abnormal hepatic free fatty acid composition was present in both the HF and H1N offspring, while the H9N offspring displayed both at normal levels. These physiological changes were associated with desensitized hepatic insulin/AKT signaling, increased expression of genes and proteins for de novo lipogenesis and cholesterol synthesis, decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression, and hypoactivation of 5' AMP-activated protein kinase (AMPK) signaling in the HF and H1N offspring. However, these effects were completely or partially rescued in the H9N offspring. In summary, we found that early maternal diet intervention is effective in reducing the risk of offspring NAFLD caused by maternal HF diet. These findings provide significant support to develop effective diet intervention strategies and policies for prevention of obesity and NAFLD to promote optimal health outcomes for mothers and children.

A long-term maternal diet intervention is necessary to avoid the obesogenic effect of maternal high-fat diet in the offspring.

Although a pre-pregnancy dietary intervention is believed to be able to prevent offspring obesity, research evidence is absent. We hypothesize that a long period of pre-pregnancy maternal diet transition from a high-fat (HF) diet to a normal-fat (NF) diet effectively prevents offspring obesity, and this preventive effect is independent of maternal body weight change. In our study, female mice were either continued on an NF diet (NF group) or an HF diet (HF group) until weaning, or switched from an HF to an NF for 1 week (H1N group), 5 weeks (H5N group) or 9 weeks (H9N group) before pregnancy. After weaning, the offspring were given the HF diet for 12 weeks to promote obesity. The mothers, regardless of which group, did not display maternal body weight change and glucose intolerance either before pregnancy or after weaning. Compared to the HF group, the H1N and H5N, but not the H9N, offspring developed glucose intolerance earlier, with more severely imbalanced glucose homeostasis. These offspring also displayed hepatocyte degeneration and significant adipocyte hypertrophy associated with higher expression of lipogenesis genes. The molecular mechanistic study showed blunted insulin signaling, overactivated adipocyte Akt signaling and hepatic AMPK signaling with enhanced lipogenesis genes in the H1N and H5N versus the NF offspring. However, maternal H9N diets normalized glucose and lipid metabolism of the offspring via resensitized insulin signaling and normalized Akt and AMPK signaling. In summary, we showed that a long-term maternal diet intervention effectively released the intergenerational obesogenic effect of maternal HF diet independent of maternal weight management.