N6 -Methyladenosine Reader Protein YT521-B Homology Domain-Containing 2 Suppresses Liver Steatosis by Regulation of mRNA Stability of Lipogenic Genes.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. APPROACH AND RESULTS: In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. CONCLUSIONS: Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.

Identifying Acss1, Mtfp1 and Oxct1 as key regulators and promising biomarkers of sarcopenia in various models.

Mitochondrial dysfunction plays a critical role in muscular homeostasis, but the molecular mechanism underlying mitochondrial dynamics and sarcopenia awaits to be uncovered. We all know that malnutrition, cachexia, and type 2 diabetes are significant contributors to the development of sarcopenia.Therefore, we analyzed a bioinformatic analysis on cathectic differentially expressed genes (cDEGs), fasted differentially genes (fDEGs) and mitochondria-related genes. The overlapping genes identified were then validated by RT-qPCR and Western blotting experiments in various sarcopenia mice models and used to predict aging-related muscle loss in humans. First, the correlation analysis and PPI network indicated 6 overlapping candidates (Bdh1, Gdap1, Acss1, Mtfp1, Idh2, Oxct1) may constitute a regulatory effect in mitochondrial dynamics and muscle wasting. Next, we successfully established fasted, Lewis lung carcinoma (LLC) and Diabetes Mellitus (DM) induced sarcopenia mice models and verified that Acss1, Mtfp1 and Oxct1 shared common and significant variation tendency in these sarcopenia mice models. Further-more, Pearson correlation analysis showed that Acss1 was negatively related to the weight of gastrocnemius while Mtfp1 and Oxct1 displayed a significantly positive correlation with gastrocnemius weight in sarcopenic mice model induced by LLC, fasting and DM. What's more, ROC analysis based on human aging-related datasets indicated Acss1, Mtfp1, Oxct1 had outstanding diagnostic capabilities for sarcopenia. In general, we identified three hub genes (Acss1, Mtfp1 and Oxct1) that are strongly associated with mitochondrial dysfunction in sarcopenia and may provide novel and reliable indicators for screening, diagnosis, and prognosis, as well as potential therapeutic targets for patients with sarcopenia.

Ecotoxicity of thallium to two soil animal species with different niches and modification by organic materials.

Soil thallium (Tl) contamination is of major public concern but little is known about soil Tl ecological toxicity or potential ecological remediation strategies. Here, two soil animal species with different ecological niches, Folsomia candida and Enchytraeus crypticus, were used to test Tl toxicity and modification by exogenous organic materials (i.e. maize straw and biochar). The endpoints of Tl ecotoxicity to F. candida and E. crypticus were studied at two biological levels, i.e., the individual (body Tl concentrations) and the population (survival, reproduction, and growth). Thallium concentrations in F. candida and E. crypticus increased with increasing soil Tl concentration, and their survival and reproduction rates decreased with increasing soil Tl concentration. The LC50 value of Tl effects on F. candida mortality (28 d) was 24.0 mg kg-1 and the EC50 value of reproduction inhibition was 6.51 mg kg-1. The corresponding values were 4.15 mg kg-1 and 2.31 mg kg-1 respectively for E. crypticus showing higher sensitivity to soil Tl than F. candida. These effective values are comparable to or much lower than the environmental Tl concentrations in field soils, suggesting high potential ecological risk. Both biochar and straw can decrease animal body Tl concentrations in different ways, i.e. reducing Tl availability or offering clean food sources, and addition of exogenous organic materials clearly mitigated Tl ecotoxicity in highly polluted soil. The results highlight the potential Tl ecological risk to soil animals and the potential use of organic materials to control the toxicity.

Modelling the epidemic dynamics of COVID-19 with consideration of human mobility.

So far COVID-19 has resulted in mass deaths and huge economic losses across the world. Various measures such as quarantine and social distancing have been taken to prevent the spread of this disease. These prevention measures have changed the transmission dynamics of COVID-19 and introduced new challenges for epidemic modelling and prediction. In this paper, we study a novel disease spreading model with two important aspects. First, the proposed model takes the quarantine effect of confirmed cases on transmission dynamics into account, which can better resemble the real-world scenario. Second, our model incorporates two types of human mobility, where the intra-region human mobility is related to the internal transmission speed of the disease in the focal area and the inter-region human mobility reflects the scale of external infectious sources to a focal area. With the proposed model, we use the human mobility data from 24 cities in China and 8 states in the USA to analyse the disease spreading patterns. The results show that our model could well fit/predict the reported cases in both countries. The predictions and findings shed light on how to effectively control COVID-19 by managing human mobility behaviours.

Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor.

Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.

Stanniocalcin 2 Ameliorates Hepatosteatosis Through Activation of STAT3 Signaling.

Stanniocalcin 2 (STC2), a secreted glycoprotein hormone, regulates many biological processes, including cell proliferation, apoptosis, tumorigenesis, and atherosclerosis. However, its role in hepatic triglyceride metabolism remains unknown. In the present study, we found that expression levels of STC2 were significantly reduced in the livers of leptin-deficient and high fat diet-induced obese mice. Systemic administration of STC2 recombinant protein or adenovirus-mediated overexpression of STC2 markedly attenuated hepatosteatosis and hypertriglyceridemia in obese mice. At the molecular level, we found that STC2 activated the STAT3 signaling pathway to inhibit lipogenic gene expression. Consistently, in vitro studies further showed that inhibition of STAT3 signaling abolished the anti-steatotic effects of STC2. Together, our results revealed an important role of STC2 in the regulation of hepatic triglyceride metabolism, which might provide a potential therapeutic target for the treatment of fatty liver and related metabolic disorders.

Elevated Serum Growth Differentiation Factor 15 Levels in Hyperthyroid Patients.

Background: Recent studies have shown that growth differentiation factor 15 (GDF15), a member of the transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) superfamily, plays an important role in appetite, type 2 diabetes, and cardiovascular diseases. Since thyroid hormone has pleiotropic effects on whole-body energy metabolism, we aimed to explore the effect of thyroid hormone on circulating GDF15 levels in humans and GDF15 genes expression in C57BL/6 mice. Methods: A total of 134 hyperthyroid patients and 105 healthy subjects were recruited. Of them, 43 hyperthyroid patients received thionamide treatment for 3 months until euthyroidism. Serum GDF15 levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. To determine the source for the increased circulating GDF15, C57BL/6 mice were treated with T3, and GDF15 gene expressions in the liver, skeletal muscle, brown adipose tissue (BAT), inguinal white adipose tissue (iWAT), epididymal white adipose tissue (eWAT) were analyzed by quantitative real-time polymerase chain reaction (PCR). Results: Serum GDF15 levels were significantly elevated in hyperthyroid patients as compared with healthy subjects (326.06 ± 124.13 vs. 169.24 ± 82.96 pg/mL; P < 0.001). After thionamide treatment, GDF15 levels in hyperthyroid patients declined markedly from 293.27 ± 119.49 to 118.10 ± 71.83 pg/mL (P < 0.001). After adjustment for potential confounders, serum GDF15 levels were independently associated with hyperthyroidism. T3 treatment increased GDF15 expression in the brown adipose tissue of C57BL/6 mice. Conclusions: Serum GDF15 levels were elevated in patients with hyperthyroidism and declined after thionamide treatment. Thyroid hormone treatment upregulated GDF15 expression in mice. Therefore, our results present the clinical relevance of GDF15 in humans under the condition of hyperthyroidism.

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c.

Obesity is usually associated with an increased risk of nonalcoholic fatty liver disease that is characterized by accumulation of excessive triglyceride (TG) in hepatocytes. However, the factors involved in the obesity-induced hepatosteatosis are poorly defined. Here, we report that SRY-box containing gene 4 (Sox4), a transcription factor that regulates cell proliferation and differentiation, plays an important role in hepatic TG metabolism. Sox4 expression levels are markedly upregulated in livers of obese rodents and humans. Adenovirus-medicated overexpression of Sox4 in the livers of lean mice promotes liver steatosis, whereas liver-specific knockdown of Sox4 ameliorates TG accumulation and improves insulin resistance in obese mice. At the molecular level, we show that Sox4 could directly control the transcription of SREBP-1c gene through binding to its proximal promoter region. Thus, we have identified Sox4 as an important component of hepatic TG metabolism.

Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A.

Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet-induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis.

Stanniocalcin2 acts as an anorectic factor through activation of STAT3 pathway.

The regulation of food intake and body weight has been hotly investigated. In the present study, we show that stanniocalcin2 (STC2), a cytokine ubiquitously expressed and especially upregulated in many types of human cancers, has a regulatory role in food intake and weight loss. Systemic treatment of C57BL/6 mice with recombinant STC2 protein resulted in decreased food intake and body weight, whereas energy expenditure was not affected. Similarly, STC2 treatment also induced anorexia in hyperphagic leptin-deficient mice, leading to a significant reduction in body weight and improvement of blood glucose levels. Furthermore, intracerebroventricular administration of STC2 to mice led to an acute decrease in food intake, which was mediated, at least in part, by activation of STAT3 pathway. Taken together, our results revealed the importance of STC2 in the regulation of feeding behavior as well as body weight.

MicroRNA-124 promotes hepatic triglyceride accumulation through targeting tribbles homolog 3.

An increase in hepatic triglyceride (TG) contents usually results in non-alcoholic fatty liver disease (NAFLD) and related metabolic diseases. However, the mechanisms underlying perturbations of hepatic TG homeostasis remain largely unknown. Here, we showed that MicroRNA-124 was up-regulated in the livers of C57BL/6 mice fed a short-term high-fat-diet (HFD). Adenoviral overexpression of miR-124 in C57BL/6 mice led to accumulation of excessive triglycerides and up-regulation of lipogenic genes in the liver. We further identified tribbles homolog 3 (TRB3) as a direct target of miR-124. AKT signaling, which is negatively regulated by TRB3, was enhanced by miR-124 overexpression. Moreover, restoration of TRB3 expression markedly abolished the effect of miR-124 on hepatic TG metabolism. Therefore, our findings revealed that miR-124 played a role in mediating high-fat-diet induced TG accumulation in the liver.

Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring.

Both epidemiologic and experimental animal studies demonstrate that chronic psychological stress exerts adverse effects on the initiation and/or progression of many diseases. However, intergenerational effects of this environmental information remains poorly understood. Here, using a C57BL/6 mouse model of restraint stress, we show that offspring of stressed fathers exhibit hyperglycemia due to enhanced hepatic gluconeogenesis and elevated expression of PEPCK. Mechanistically, we identify an epigenetic alteration at the promoter region of the Sfmbt2 gene, a maternally imprinted polycomb gene, leading to a downregulation of intronic microRNA-466b-3p, which post-transcriptionally inhibits PEPCK expression. Importantly, hyperglycemia in F1 mice is reversed by RU486 treatment in fathers, and dexamethasone administration in F0 mice phenocopies the roles of restraint stress. Thus, we provide evidence showing the effects of paternal psychological stress on the regulation of glucose metabolism in offspring, which may have profound implications for our understanding of health and disease risk inherited from fathers.