CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis.

Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders.

Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway. / ç»†èƒžå› å­å—ä½“æ ·å› å­1(CRLF1)通过ERK1/2信号通路促进心脏纤维化.

Cardiac fibrosis is a cause of morbidity and mortality in people with heart disease. Anti-fibrosis treatment is a significant therapy for heart disease, but there is still no thorough understanding of fibrotic mechanisms. This study was carried out to ascertain the functions of cytokine receptor-like factor 1 (CRLF1) in cardiac fibrosis and clarify its regulatory mechanisms. We found that CRLF1 was expressed predominantly in cardiac fibroblasts. Its expression was up-regulated not only in a mouse heart fibrotic model induced by myocardial infarction, but also in mouse and human cardiac fibroblasts provoked by transforming growth factor-|ß1 (TGF|-|ß1). Gain- and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-|ß1 stimulation. CRLF1 overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF|-|ß1 stimulation, while silencing of CRLF1 had the opposite effects. An inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and different inhibitors of TGF-|ß1 signaling cascades, comprising mothers against decapentaplegic homolog (SMAD)|-dependent and SMAD-independent pathways, were applied to investigate the mechanisms involved. CRLF1 exerted its functions by activating the ERK1/2 signaling pathway. Furthermore, the SMAD-dependent pathway, not the SMAD-independent pathway, was responsible for CRLF1 up-regulation in NMCFs treated with TGF-|ß1. In summary, activation of the TGF-|ß1/SMAD signaling pathway in cardiac fibrosis increased CRLF1 expression. CRLF1 then aggravated cardiac fibrosis by activating the ERK1/2 signaling pathway. CRLF1 could become a novel potential target for intervention and remedy of cardiac fibrosis.

Associations of Menstrual Cycle Regularity and Length With Cardiovascular Diseases: A Prospective Study From UK Biobank.

Background The association between menstrual cycle characteristics and cardiovascular outcomes remains unclear. This study was undertaken to evaluate whether menstrual cycle regularity and length throughout the life course are associated with cardiovascular outcomes. Methods and Results This cohort study included 58 056 women who had no cardiovascular disease (CVD) at baseline and reported their menstrual cycle regularity and length. Hazard ratios (HRs) and 95% CIs for CVD events were estimated using Cox proportional hazards models. During the median 11.8 years of follow-up, 1623 incident CVD cases were documented, including 827 incident cases of coronary heart disease, 199 myocardial infarctions, 271 strokes, 174 cases of heart failure, and 393 cases of atrial fibrillations. Compared with women with regular menstrual cycles, the HRs for women with irregular menstrual cycles were 1.19 (95% CI, 1.07-1.31) for CVD events and 1.40 (95% CI, 1.14-1.72) for atrial fibrillation. The multivariable-adjusted HRs for short (≤21 days) or long (35 days) menstrual cycles during follow-up were 1.29 (95% CI, 1.11-1.50) and 1.11 (95% CI, 0.98-1.56) for CVD events, respectively. Similarly, long or short cycle length were more likely to be associated with increased risk of atrial fibrillation (HR, 1.30 [95% CI, 1.01-1.66]; and HR, 1.38 [95% CI, 1.02-1.87]), and short cycle length was more likely to be associated with increased risk of coronary heart disease and myocardial infarction. However, these associations for stroke and heart failure were not significant. Conclusions Long or short menstrual cycle length was associated with increased risks of CVD and atrial fibrillation but not myocardial infarction, heart failure, or stroke. Short cycle length was associated with a greater risk of coronary heart disease and myocardial infarction.

Circulating galectin-3 levels are inversely associated with subclinical cardiovascular disease in obese adults.

BACKGROUND: Galectin-3 is a new cytokine that is mainly secreted by activated macrophages. It is involved in apoptosis, inflammation and may play a role in the development of cardiovascular disease (CVD). However, there is little information about the association between circulating galectin-3 and subclinical atherosclerosis in humans. METHODS AND RESULTS: We measured serum galectin-3 in 483 obese adult subjects (aged 40 years and over) who had the measurement of carotid intima-media thickness (CIMT) recruited from the community. Adults with lower levels of circulating galectin-3 had increased CIMT (p < 0.05). In multivariable linear regression analyses, circulating galectin-3 was independently associated with CIMT. The risks of increased CIMT were significantly decreased by 65.1% (OR (95% CI): 0.349 (0.165-0.739)), adjusting for possible confounding factors. Notably, individuals in the lowest quartile of serum galectin-3 were 1.80 times (p < 0.05) more likely to have increased CIMT than those in the highest quartile in multivariable logistic regression analyses; however, such associations with circulating galectin-3 were not noted for carotid plague. CONCLUSIONS: These findings propose that circulating galectin-3 concentrations are inversely associated with increased CIMT in obese adults, which may be a potential biomarker of CVD.

High-quality all-inorganic CsPbBr3 single crystals prepared by a facile one-step solution growth method.

In this report, a facile one-step solution growth method has been proposed to synthesize high-quality all-inorganic CsPbBr3 single crystals. High-resolution X-ray diffraction, photoluminescence (PL), and current-voltage techniques have been performed to study the properties of CsPbBr3 single crystals. The results have shown that the as-grown CsPbBr3 single crystals exhibited a narrow X-ray rocking curve with a FWHM (full width at half maximum) of 0.043°, a narrow room-temperature PL spectrum with the FWHM of 18.9 nm, and extremely low density of traps (∼5.1 × 109 cm-3). The results shown in this work will provide a valuable strategy for the fabrication of high-quality all-inorganic CsPbBr3 single crystals.

Leukemia inhibitory factor protects against liver steatosis in nonalcoholic fatty liver disease patients and obese mice.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. However, the molecular mechanisms that promote dysregulation of hepatic triglyceride metabolism and lead to NAFLD are poorly understood, and effective treatments are limited. Leukemia inhibitory factor (LIF) is a member of the interleukin-6 cytokine family and has been shown to regulate a variety of physiological processes, although its role in hepatic triglyceride metabolism remains unknown. In the present study, we measured circulating LIF levels by ELISA in 214 patients with biopsy-diagnosed NAFLD as well as 314 normal control patients. We further investigated the potential role and mechanism of LIF on hepatic lipid metabolism in obese mice. We found that circulating LIF levels correlated with the severity of liver steatosis. Patients with ballooning, fibrosis, lobular inflammation, and abnormally elevated liver injury markers alanine transaminase and aspartate aminotransferase also had higher levels of serum LIF than control patients. Furthermore, animal studies showed that white adipose tissue-derived LIF could ameliorate liver steatosis through activation of hepatic LIF receptor signaling pathways. Together, our results suggested that targeting LIF-LIF receptor signaling might be a promising strategy for treating NAFLD.

Circulating adipsin is associated with asymptomatic carotid atherosclerosis in obese adults.

BACKGROUND: Adipsin has been identified as a secreted adipokine that plays a critical pathogenic role in metabolic disorders. However, it is not clear regarding the association of circulating adipsin with cardiovascular disease (CVD). This study will explore the association between circulating adipsin and asymptomatic carotid atherosclerosis in Chinese obese adults. METHODS: A total of 483 obese adult subjects (aged 40 years or older) were enrolled in this study. Serum adipsin concentrations and carotid intima-media thickness (CIMT) were measured to determine these associations. RESULTS: Individuals with increased CIMT and asymptomatic carotid atherosclerosis had lower levels of circulating adipsin than controls (both p < 0.05). The prevalence of asymptomatic carotid atherosclerosis was significantly higher in subjects with lower levels of serum adipsin than those with higher values (42.5% vs. 36.7%, p < 0.05). Notably, subjects in the lowest quartile of serum adipsin were 1.94 times (p = 0.059) more likely to have increased CIMT and 2.91 times (p = 0.03) more likely to have asymptomatic carotid atherosclerosis than those in the highest quartile in multivariable logistic regression analyses, adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic BP, fasting glucose, total cholesterol, HDL-c, and HOMA-IR. However, such associations with circulating adipsin were not noted for atherosclerotic plaque. CONCLUSIONS: These findings suggest that circulating adipsin concentrations are a potential marker of risks of increased CIMT and asymptomatic carotid atherosclerosis in obese Chinese adults.

Association of circulating adipsin with nonalcoholic fatty liver disease in obese adults: a cross-sectional study.

BACKGROUND: As a secreted adipokine, adipsin has been recently shown to play a pivotal role in metabolic disorders. However, information regarding the association of circulating adipsin with non-alcoholic fatty liver disease (NAFLD) in humans is scant. METHODS: We recruited 1163 obese adult subjects with waist circumference at least 90 cm in men and 80 cm in women from the community. Circulating adipsin levels were measured by enzyme-linked immunosorbent assay. RESULTS: Circulating adipsin levels of NAFLD subjects was decreased compared to those in non-NAFLD (p < 0.05). The prevalence of NAFLD with lower levels of serum adipsin was significantly higher than those with higher values (57.6% vs. 50.9%, p < 0.05). Circulating adipsin levels were significantly associated with decreasing levels of fasting glucose and postprandial glucose (both p < 0.001 for interaction) in NAFLD subjects but not in non-NAFLD subjects. The risk of NAFLD was significantly decreased by 21.7% [OR (95% CI): 0.783 (0.679-0.902), p < 0.001], adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic BP, fasting glucose, total cholesterol, HDL-c, HOMA-IR, and body fat mass. Importantly, subjects in the lowest quartile of circulating adipsin were 1.88 times more likely to have NAFLD than those in the highest quartile in multivariable logistic regression analyses. However, such associations with circulating adipsin were not noted for metabolic syndrome, abnormal liver enzyme and significant liver fibrosis. CONCLUSIONS: These results demonstrate that circulating adipsin levels in Chinese obese adults are negatively associated with risk of NAFLD, implying that serum adipsin levels may be a potential protective factor in NAFLD.

FOXA3 induction under endoplasmic reticulum stress contributes to non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Chronic endoplasmic reticulum (ER) stress in the liver has been shown to play a causative role in non-alcoholic fatty liver disease (NAFLD) progression, yet the underlying molecular mechanisms remain to be elucidated. Forkhead box A3 (FOXA3), a member of the FOX family, plays critical roles in metabolic homeostasis, although its possible functions in ER stress and fatty liver progression are unknown. METHODS: Adenoviral delivery, siRNA delivery, and genetic knockout mice were used to crease FOXA3 gain- or loss-of-function models. Tunicamycin (TM) and a high-fat diet (HFD) were used to induce acute or chronic ER stress in mice. Chromatin immunoprecipiation (ChIP)-seq, luciferase assay, and adenoviral-mediated downstream gene manipulations were performed to reveal the transcriptional axis involved. Key axis protein levels in livers from healthy donors and patients with NAFLD were assessed via immunohistochemical staining. RESULTS: FOXA3 transcription is specifically induced by XBP1s upon ER stress. FOXA3 exacerbates the excessive lipid accumulation caused by the acute ER-inducer TM, whereas FOXA3 deficiency in hepatocytes and mice alleviates it. Importantly, FOXA3 deficiency in mice reduced diet-induced chronic ER stress, fatty liver, and insulin resistance. In addition, FOXA3 suppression via siRNA or adeno-associated virus delivery ameliorated the fatty liver phenotype in HFD-fed and db/db mice. Mechanistically, ChIP-Seq analysis revealed that FOXA3 directly regulates Period1 (Per1) transcription, which in turn promotes the expression of lipogenic genes, including Srebp1c, thus enhancing lipid synthesis. Of pathophysiological significance, FOXA3, PER1, and SREBP1c levels were increased in livers of obese mice and patients with NAFLD. CONCLUSION: The present study identified FOXA3 as the bridging molecule that links ER stress and NAFLD progression. Our results highlighted the role of the XBP1s-FOXA3-PER1/Srebp1c transcriptional axis in the development of NAFLD and identified FOXA3 as a potential therapeutic target for fatty liver disease. LAY SUMMARY: The molecular mechanisms linking endoplasmic reticulum stress to non-alcoholic fatty liver disease (NAFLD) progression remain undefined. Herein, via in vitro and in vivo analysis, we identified Forkhead box A3 (FOXA3) as a key bridging molecule. Of pathophysiological significance, FOXA3 protein levels were increased in livers of obese mice and patients with NAFLD, indicating that FOXA3 could be a potential therapeutic target in fatty liver disease.

The S100 calcium-binding protein A11 promotes hepatic steatosis through RAGE-mediated AKT-mTOR signaling.

RATIONALE: Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, has become an increasingly severe public health problem. However, the underlying mechanism for the occurrence and development of NAFLD remains largely unknown. S100 calcium-binding protein A11 (S100A11) is a multifunctional protein previously reported to be a poor prognostic indicator of hepatocellular carcinoma, while the role of S100A11 affects NAFLD is still not clear. METHODS: Immunohistochemical staining was performed using human NAFLD and control biopsy specimens. Serum level of S100A11 were analyzed by Elisa assays. The S100A11 over-expressed/ knocked-down model was established in vitro or in vivo. The expression levels of genes related to lipid metabolism in liver tissue were performed by quantitative PCR and western blotting. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. RESULTS: We showed that the concentration of serum S100A11 was significantly elevated in NAFLD patients, and expression of S100A11 was remarkedly increased in the livers of NAFLD patients and mouse models. Overexpression of S100A11 in vivo markedly increased liver steatosis, body weight, and serum aspartate aminotransaminase (AST) levels. Mechanistically, our results demonstrated that S100A11 acted as a positive regulator of AKT/mTOR signaling to induce lipid synthesis and aggravate lipid deposition. CONCLUSIONS: These results provide evidence for a novel role of S100A11 that contributes to hepatic steatosis, suggesting that targeting S100A11 may be an alternative approach for the treatment of NAFLD.

Obesity-induced upregulation of microRNA-183-5p promotes hepatic triglyceride accumulation by targeting the B-cell translocation gene 1.

AIMS: Obesity is recognized as a risk factor for many metabolic disorders, particularly nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism is still poorly understood. Several lines of evidence indicate that microRNA (miRNA) is a key regulator of lipid metabolism. In this study, we investigated the role of miR-183-5p in the development of NAFLD. METHODS: The expression levels of miR-183-5p and B-cell translocation gene 1 (Btg1) were determined by quantitative real-time PCR and histological analysis in livers of obese mice and cell models induced with palmitic acid (PA), respectively. AML12 cells were treated with PA in the presence or absence of miR-183-5p mimics or inhibitor. Moreover, a Luciferase reporter assay was used to determine whether Btg1 is the direct target of miR-183-5p. Protein levels of BTG1 were estimated using western blotting. KEY FINDINGS: Expression of miR-183-5p was increased in the livers of three murine models and also in the AML12 cell model. Overexpression of miR-183-5p in the cell model and mice led to hepatic triglyceride (TG) accumulation and upregulation of lipogenic genes, whereas inhibition of miR-183-5p in the cell model improved hepatic TG accumulation. Mechanistically, we further identified Btg1 as a direct target gene of miR-183-5p. SIGNIFICANCE: Our findings revealed that miR-183-5p affected the regulation of hepatic TG homeostasis, which may provide a potential therapeutic target for hepatosteatosis.

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.

The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36.

Nuclear receptors (NRs) are a superfamily of transcription factors which sense hormonal signals or nutrients to regulate various biological events, including development, reproduction, and metabolism. Here, this study identifies nuclear receptor subfamily 2, group F, member 6 (NR2F6), as an important regulator of hepatic triglyceride (TG) homeostasis and causal factor in the development of non-alcoholic fatty liver disease (NAFLD). Adeno-associated virus (AAV)-mediated overexpression of NR2F6 in the liver promotes TG accumulation in lean mice, while hepatic-specific suppression of NR2F6 improves obesity-associated hepatosteatosis, insulin resistance, and methionine and choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH). Mechanistically, the fatty acid translocase CD36 is identified as a transcriptional target of NR2F6 to mediate its steatotic role. NR2F6 is able to bind directly onto the CD36 promoter region in hepatocytes and increases the enrichment of nuclear receptor coactivator 1 (SRC-1) and histone acetylation at its promoter. Of pathophysiological significance, NR2F6 is significantly upregulated in the livers of obese mice and NAFLD patients. Moreover, treatment with metformin decreases NR2F6 expression in obese mice, resulting in suppression of CD36 and reduced hepatic TG contents. Therefore, these results provide evidence for an unpredicted role of NR2F6 that contributes to liver steatosis and suggest that NR2F6 antagonists may present a therapeutic strategy for reversing or treating NAFLD/NASH pathogenesis.

Boosting the performance of ZnO microrod metal-semiconductor-metal photodetectors via surface capping of thin amorphous Al2O3 shell layer.

1D ZnO nanostructures have been widely explored due to their potential applications in ultraviolet (UV) region photodetectors because of their unique structural and optoelectronic properties. However, a large number of surface defect states leading to a noticeable dark current hinders their practical applications in UV photodetection. In this work, we have shown improved ZnO/Al2O3 core-shell microrod photodetectors, whose performance is significantly enhanced by defect passivation and the introduction of trap states by atomic layer deposition grown thin amorphous Al2O3 shell layer, as evidenced by steady-state and transient photoluminescence investigations. The photodetectors demonstrated suppressed dark current and increased photocurrent after capping the Al2O3 layer. Specifically, the ZnO/Al2O3 core-shell microrod photodetector exhibited a photoresponsivity as high as 0.019 A/(W cm-2) with the dark current as low as ∼1 × 10-11 A, and a high I light/I dark ratio of ∼104 under relatively weak light illumination (∼10 µW cm-2). The results presented in this work provide valuable pathways to boost the performance of 1D ZnO microrod-based photodetectors for future practical applications.

[Surgical treatment of transcranial middle cranial fossa-lateral skull base malignant tumor].

OBJECTIVE: To evaluate the surgical method of transcranial middle cranial fossa-lateral skull base malignant tumor. METHODS: Sixteen patients with transcranial middle cranial fossa-lateral skull base malignant tumors were treated by three surgical methods. (1) Postauricular "C" form incision, combined with subtotal resection of temporal bone and high lateral neck approach to resect tumors located in middle cranial fossa, lateral skull base, and parotid region. (2) Temporal side "tungue" form incision, middle cranial fossa approach to resect tumors inside and outside the skull. (3) Temporal-auricular-mandible swing approach to resect tumors in parapharyngeal-infratemporal fossa-middle cranial fossa. Thirteen of the 16 cases received radiotherapy postoperatively. RESULTS: After operation, 11 of the 16 cases survived more than three years, five cases died within three years. Three-year-survival rate was 69%. CONCLUSIONS: Our results showed that the three surgical methods adopted could fully expose the internal and external skull lesion to remove the extensive malignant tumors. For late stage malignant tumors of the skull base, it should be treated aggressively by combination of surgical therapy and postoperative radiotherapy.

[Resection of malignant tumors of the anterior skull base and the fronto-orbito-ethmoidal region by overturn of frontonasal flap].

OBJECTIVE: To introduce a better surgical approach for the resection of malignant tumors in the anterior skull base and in the fronto-orbito-ethmoidal region. METHODS: A "U" form incision on the bilateral superciliary arch was made and connected with the unhealthy nasal side incision. Then the frontal musculocutaneous flap was over-turned upward. The nasal pyramid was over-turned to the healthy side. The malignant tumors in the anterior skull base and the fronto-orbito-ethmoidal region were fully exposed and resected. RESULTS: From december 1986 to december 1996, 50 patients received tumour resection through this approach. Postoperatively, the one-year survival rate was 86.0% (43/50), the three-year survival rate was 62.0% (31/50), and the five-year survival rate was 44.0% (22/50). CONCLUSION: The frontonasal flap overturn approach provided good exposure of surgical field, avoided the coronal incision, and the reaction of brain was mild. We believe this surgical approach is superior to traditional combined craniofacial approach.