Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming.

Thermogenic adipocytes have been extensively investigated because of their energy-dissipating property and therapeutic potential for obesity and diabetes. Besides serving as fuel sources, accumulating evidence suggests that intermediate metabolites play critical roles in multiple biological processes. However, their role in adipocyte differentiation and thermogenesis remains unexplored. Here, we report that human and mouse obesity is associated with marked downregulation of glutamine synthetase (Glul) expression and activity in thermogenic adipose tissues. Glul is robustly upregulated during brown adipocyte (BAC) differentiation and in brown adipose tissue (BAT) upon cold exposure and Cl316,243 stimulation. Further genetic, pharmacologic, or metabolic manipulations of Glul and glutamine levels reveal that glutamine cells autonomously stimulate BAC differentiation and function and BAT remodeling and improve systemic energy homeostasis in mice. Mechanistically, glutamine promotes transcriptional induction of adipogenic and thermogenic gene programs through histone modification-mediated chromatin remodeling. Among all the glutamine-regulated writer and eraser genes responsible for histone methylation and acetylation, only Prdm9, a histone lysine methyltransferase, is robustly induced during BAC differentiation. Importantly, Prdm9 inactivation by shRNA knockdown or a selective inhibitor attenuates glutamine-triggered adipogenic and thermogenic induction. Furthermore, Prdm9 gene transcription is regulated by glutamine through the recruitment of C/EBPb to its enhancer region. This work reveals glutamine as a novel activator of thermogenic adipocyte differentiation and uncovers an unexpected role of C/EBPb-Prdm9-mediated H3K4me3 and transcriptional reprogramming in adipocyte differentiation and thermogenesis.

Characteristics of steroid hormones in systemic lupus erythematosus revealed by GC/MS-based metabolic profiling.

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a remarkable predominance in female, suggesting that steroid hormones may be involved in the pathogenesis. However, steroid signature of SLE patients has not been fully explored. Methods: A metabolic profiling analysis based on gas chromatography/mass spectrometry (GC/MS) with high sensitivity and reproducibility was employed to comprehensively reveal SLE-specific steroid alterations. Results: More than 70 kinds of steroids in urine were detected by gas chromatography/mass spectrometry (GC/MS) to reveal SLE-specific steroid alterations. Principle component analysis demonstrated that the steroid profile was obviously distinguished between patients with SLE and controls. A lower level of total androgens was observed in patients, and nine androgens [dehydroepiandrosterone (DHEA), testosterone, Etio, androsterone, ßαß-Diol, Epi-An, Epi-DHT, 16α-OH-DHEA, and A-Diol] underwent significant decrease. Moreover, patients with SLE exhibited a slightly higher level of total estrogens than controls, and three estrogens (17-Epi-E3, 17α-E2, and E3) were remarkably increased. Furthermore, we identified the elevation of two sterols (Lan and Chol), and the reduction of one corticoid (11-DeoxyF) and two progestins (5α-DHP and 11ß-OH-Prog) in patients. Discussion: In this study, metabolic signature of urinary steroids associated with SLE was comprehensively defined by GC/MS for the first time, and steroid metabolism disorders were found in patients with SLE, especially the conversion of androgens to estrogens. Our findings will provide new insights for a deeper understanding of the mechanism of steroid hormones in the pathogenesis of SLE and will help to unravel the reason of sexual disparity in SLE.

The Burden of Diabetes-Related Chronic Kidney Disease in China From 1990 to 2019.

Objective: To analyze the trends in disease burden of diabetes-related chronic kidney disease (CKD) by year, age, gender and types of diabetes in China from 1990 to 2019. Methods: Data on prevalence, deaths and disability-adjusted life years (DALYs) for diabetes-related CKD were extracted from the Global Burden of Disease (GBD) 2019 study. Analyses were performed by year, age, gender and types of diabetes. Results: In China, the numbers of deaths and DALYs of diabetes-related CKD continuously increased but the age-standardized rates (per 100,000 population) decreased over 30 years, in which the numbers of deaths and DALYs attributable to type 1 diabetes mellitus (T1DM)-related CKD barely changed and the age-standardized rates decreased over the years; and the number of deaths and DALYs attributable to type 2 diabetes mellitus (T2DM)-related CKD continuously increased, but the age-standardized rates also decreased. In 2019, 76.03 (58.24-95.61) thousand deaths and 2.13 (1.65-2.67) million DALYs were attributable to diabetes-related CKD, of which, T2DM accounted for 83.32% and 77.0% respectively, and T1DM accounted for the rest. Increasing gender disparity was seen, with males being more heavily impacted. The burden of diabetes-related CKD varied among different age groups, with the numbers of deaths and DALYs attributable to T1DM-related CKD peaking between 45 and 54 years of age and T2DM-related CKD peaking between 75 and 79 years of age; and the crude rates of deaths and DALYs attributable to T1DM-related CKD peaking between 70 and 79 years of age and 40 to 54 years of age, respectively, and T2DM-related CKD peaking over 90 years of age. Among neighboring and G20 countries, the burden of diabetes-related CKD in China was relatively controlled reflected by the ranking of adjusted death and DALYs rates. Conclusions: The burden of diabetes-related CKD in China worsens and shows gender disparities and different age distribution. Greater efforts are needed to improve the health outcomes of these patients, especially among males.

Socioeconomic disparity in global vision loss burden due to diabetic retinopathy: an analysis on time trends from 1990 to 2017.

PURPOSE: To describe the trends of socioeconomic disparity in global vision loss burden associated with diabetic retinopathy (DR) based on prevalence and years lived with disability (YLDs). METHODS: In the Global Burden of Disease (GBD) 2017 study, we extracted global, regional, national, and World Bank categorical epidemiological data in vision impairment by time and age. We searched the Human development index (HDI) from the Human Development Report. Pearson correlation, linear regression, and Kruskal-Wallis test were conducted to analyze the correlation between YLD rates and HDI. We used the Gini coefficient and concentration index to evaluate the socioeconomic inequality trendency. RESULTS: The global and World Bank categorical prevalence and YLDs increased from 1990 to 2017, and rose with ageing. The age-standardized prevalence and YLD rates varied geographically and highest in the Eastern Mediterranean countries. Higher vision loss burden of DR was concentrated in countries with medium level of socioeconomic development, including lower/upper middle-income and medium/high-HDI countries. The Gini coefficient decreased from 0.572 in 1990 to 0.542 in 2017, showing the decreasing between-country inequality. The concentration index decreased from 0.153 in 2000 to 0.061 in 2017, showing the reducing socioeconomic-associated disparity. CONCLUSION: The vision loss burden of DR increased in the past few decades, with a notable declining socioeconomic disparity since 2000. Our results highlight the necessity to provide more services to reduce the vision loss burden.

Association of Metabolic Syndrome With Prevalence of Obstructive Sleep Apnea and Remission After Sleeve Gastrectomy.

Obesity is an important risk factor for metabolic syndrome and obstructive sleep apnea (OSA). Bariatric surgery has been shown to effectively reduce weight and obesity-related comorbidities. However, the prevalence and severity of OSA in obese patients with different baseline metabolic states and the improvements of OSA after bariatric surgery remain unknown. The main aims of this study were to ascertain the prevalence of OSA in young Chinese obese patients with different metabolic states and to evaluate their respective OSA remission after laparoscopic sleeve gastrectomy. We first performed a cross-sectional study involving 123 metabolically healthy obese patients and 200 metabolically unhealthy obese patients (who had the same age and BMI ranges) to estimate the prevalence of OSA at baseline. Then we performed a retrospective study, which was registered at ClinicalTrials.gov (ref. NCT02653430) of 67 patients who underwent laparoscopic sleeve gastrectomy to evaluate the remission of OSA. Metabolically healthy and unhealthy obese patients had similar apnea-hypopnea index levels (16.6 ± 22.0 vs. 16.7 ± 18.7 events/h, P = 0.512) and prevalence of OSA (66.7% vs. 69.0%, P = 0.662). Male sex, age, waist circumference and lower liver-to-spleen ratio were independent risk factors for OSA. After laparoscopic sleeve gastrectomy, no difference was found in the decrease in body mass index (BMI) change (10.8 ± 4.8 vs. 10.8 ± 3.0 kg/m2, P = 0.996) or the decrease in the apnea-hypopnea index (18.9 ± 24.6 vs. 17.0 ± 24.0 events/h, P = 0.800). The remission of moderate-to-severe OSA was observed in the MHO (36.3%; 54.5-18.2%, P = 0.125) and MUO (32.2%; 66.1-33.9%, P = 0.001) patients. These results suggest that, in patients with obesity, metabolic syndrome does not add extra risk for the prevalence or severity of OSA. Both metabolically healthy and unhealthy obese patients could benefit equally from laparoscopic sleeve gastrectomy in terms of weight loss and obstructive sleep apnea remission.

Age, Gender and Geographic Differences in Global Health Burden of Cirrhosis and Liver Cancer due to Nonalcoholic Steatohepatitis.

Objective: Recently, Nonalcoholic Steatohepatitis (NASH) has become a major contributor to cirrhosis and liver cancer. Therefore, the Global Burden of Disease (GBD) 2017 was used to comprehensively analyze the global, regional, and national burden of cirrhosis and liver cancer due to NASH between 1990 and 2017. Methods: Data for cirrhosis and liver cancer due to NASH were extracted from the GBD study 2017. Socio-demographic Index (SDI) in 2017 was cited as indicators of socioeconomic status. ARIMA model was established to forecast the future health burden. Kruskal-Wallis test and Pearson linear correlation were adopted to evaluate the gender disparity and association with socioeconomic level. Results: From 1990-2017, the global disability-adjusted life years (DALYs) numbers of liver cancer due to NASH increased from 0.71 million to 1.46 million. The age-standardized DALYs rates of liver cancer due to NASH were negatively associated with SDI levels (r=0.-409, p<0.001). Geographically, Australasia experienced the largest increase in the burden of liver cancer due to NASH, with the age-standardized DALYs rate increasing by 143.54%. The global prevalence number of liver cancer due to NASH peaked at 60-64 years in males and at 65-69 years in females. Globally, the burden was heavier in males compared with females. Male-female-ratio of age-standardized DALYs rates in liver cancer due to NASH were positively related to SDI (r=0.303, P=0.011). Conclusion: The global burden of NASH-associated liver cancer has increased significantly since 1990, with age, gender and geographic disparity. Public awareness of liver diseases due to NASH should be emphasized.

Global burden of noncommunicable diseases attributable to high fasting plasma glucose.

BACKGROUND: Hyperglycemia is a major public health concern. An understanding of the latest trends of the global burden of noncommunicable diseases (NCDs) by high fasting plasma glucose (HFPG) is critical for determining research priorities and planning health policy. METHODS: This is a comparative burden-of-disease study. We obtained global, regional, and national data on deaths and disability-adjusted life years (DALYs) of NCDs attributable to HFPG from the Global Burden of Disease Study 2017, performed a secondary analysis of deaths and DALYs by time, age, gender, location, and specific causes, and analyzed their associations. RESULTS: In 2017, 6.39 million deaths and 166.36 million DALYs from NCDs were attributable to HFPG, accounting for 15.6% and 10.7% of all deaths and DALYs, respectively. The burden's rate decreased with time, increased with age and was significantly higher in males. A negative association was found between the sociodemographic index (SDI) and disease burden, and a positive association was found between SDI and male superiority by gender difference and gender ratio. CONCLUSIONS: The burden of NCDs attributable to HFPG has increased significantly since 1990 and varied widely across regions. Greater efforts are needed to prevent and control hyperglycemia, especially in less developed countries and among males.

The impact of shift work on glycemic characteristics assessed by CGM and its association with metabolic indices in non-diabetic subjects.

AIM: To explore the glycemic characteristics of non-diabetic shift workers and associations with metabolic indices. METHODS: In this cross-sectional study, 450 non-diabetic males, including 238 shift workers, aged 23-58 years, were recruited after a screening oral glucose tolerance test. Blood samples and anthropometric data were collected. Hundred and fifty of them finished a continuous glucose monitoring for 3-7 days. RESULTS: Compared to daytime workers, shift workers presented with larger WHR (p < 0.001), higher HOMA-IR (p < 0.001), higher hs-CRP level (p < 0.001) and worse lipid profiles. In glycemic characteristics, shift workers with normal glucose regulation had a similar mean blood glucose (MBG), daytime MBG, percentage of time of hyperglycemia, hypoglycemia, euglycemia, and fluctuation parameters, including standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursions (MAGE) and mean of daily differences (p > 0.05, respectively), while they had a higher nighttime MBG (p = 0.026) and blood glucose (BG) at 3 a.m. (p = 0.015). For subjects with impaired glucose regulation, both groups had no difference in any clinical characteristics or glycemic parameters (p > 0.05, respectively). Further regression analysis revealed the association between MBG/SDBG/MAGE/nighttime MBG/BG at 3 a.m. and age/WHR/hs-CRP/TC. CONCLUSION: For non-diabetic shift workers, the glycemic characteristic was the elevated nighttime glycemia, presented as higher nighttime MBG and BG at 3 a.m. And both metrics were closely associated with central obesity. Elevated nighttime glycemia was an early signal of glucose metabolism disorder in shift workers.