Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10^-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure, while scEMC10 overexpression decreases energy expenditure, thus promoting obesity in mouse. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 can be transported into cells where it binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.

Aims: To explore the relationship between serum growth differentiation factor 15 (GDF15) and metabolic abnormalities in Chinese pregnant women.Materials and Methods: We recruited 200 patients with gestational diabetes mellitus (GDM) and 211 matched normal control within 24–28 weeks of pregnancy. Enzyme‐linked immunosorbent assay (ELISA) was used to determine the serum GDF15 levels of all participants. Then we grouped participants according to the number of metabolic abnormalities (including blood glucose, blood lipids and blood pressure), divided them into a normal metabolic group, one metabolic abnormality group, two or more metabolic abnormalities group. Finally, multinomial logistic regression analysis was used to estimate the odds radio (OR) and 95% CIs expressing the association between GDF15 and metabolic abnormalities in pregnant women.Results: Through bivariate correlation analysis, we found that serum GDF15 is linearly correlated with glucose metabolism indices, such as 1h‐PG, 2h‐PG, HbA1c (all P < 0.05). In addition, serum GDF15 and triglycerides were linearly correlated (P < 0.05). Grouping by the number of metabolic abnormalities, we found that as GDF15 levels increased, the risk of metabolic abnormalities also increased (OR > 1), and the risk of multiple metabolic abnormalities was higher. As the number of metabolic abnormalities increased, serum GDF15 levels also were elevated (P < 0.001).Conclusions: The results suggest that serum GDF15 levels are closely associated with metabolic abnormalities in pregnant women and may be used as a predictor of metabolic abnormalities during pregnancy.

Aims/Introduction: High plasma 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid (CMPF) levels are significantly associated with type 2 diabetes mellitus, which is usually accompanied by metabolic syndrome and non‐alcoholic fatty liver disease (NAFLD) with increased triglyceride levels. Thus, we hypothesized that elevated CMPF levels might be related to lipid metabolism and NAFLD risk.Materials and Methods: Serum CMPF levels were determined using an enzyme‐linked immunosorbent assay in a total of 466 individuals, including 116 controls with no NAFLD or type 2 diabetes mellitus, 53 individuals with NAFLD but no type 2 diabetes mellitus, 151 individuals with type 2 diabetes mellitus but no NAFLD, and 146 individuals with both NAFLD and type 2 diabetes mellitus. The associations with age, blood pressure, lipid profiles, body mass index and liver injury marker levels were examined, and a meta‐analysis of non‐diabetic and diabetic groups was carried out to detect the combined effects.Results: The CMPF concentration in NAFLD patients was significantly lower than individuals without NAFLD in both the non‐diabetic group (P < 0.05) and diabetic group (P < 0.01), and correlated negatively with several parameters of liver function and the adiposity index. Meta‐analysis showed that serum CMPF levels was associated with decreased risk of NAFLD after combining the results (odds ratio 0.677, 95% confidence interval 0.552–0.831, P < 0.001). Additionally, the CMPF concentration was independently negatively associated with triglycerides and high‐density lipoprotein cholesterol in the meta‐analysis. Multiple stepwise regression analysis showed that body mass index, high‐density lipoprotein cholesterol, triglyceride level, age, sex and fasting plasma glucose were independently associated with CMPF (all P < 0.05).Conclusions: The results suggest that serum CMPF levels are negatively related to lipid metabolism and could be used to predict NAFLD development.

Purpose. This study aims to analyze the clinical characteristic of metabolic associated fatty liver disease (MAFLD) in patients with active Cushings disease (CD) and determine associations of thyroid hormones with MAFLD. Methods. Patients with active CD were included in this cross-sectional study. All subjects were assessed for hepatic steatosis by abdominal ultrasonography and thyroid functions. Demographic and clinical characteristic parameters were collected for correlation analysis and logistic analysis. Results. 290 individuals with active CD were included in Huashan hospital from January 2014 to February 2022. We found that the prevalence of CD with MAFLD was 33.79. The MAFLD group had a lower level of FT4 and a higher level of FT3/FT4 but no difference in levels of cortisol, 24h UFC, TSH, TT4, TT3, and FT3. Correlation analysis showed positive associations of TSH, TT4, TT3, FT3, and FT3/FT4 with BMI. In age-, BMI-, sex-, cortisol-, and 24h UFC-adjusted analysis, FT4 was independently associated with MAFLD in patients with CD. This association remained similar even after adjusting for the presence of metabolic syndrome components. Conclusion. Lower FT4 levels were associated with higher risk of MAFLD in patients with CD. FT4 may be used as a helpful indicator to predict MAFLD and provide novel ideas for the treatment of MAFLD in patients with CD in the future.

Background: Spexin is a novel peptide hormone and has shown antinociceptive effects in experimental mice. This study is aimed at evaluating the association of serum spexin level with diabetic peripheral neuropathy (DPN) and related pain in a Chinese population.Methods: We enrolled 167 type 2 diabetes mellitus (T2DM) including 56 patients without DPN (non‐DPN), 67 painless DPN, and 44 painful DPN. Serum spexin was measured using ELISA. Logistic regression models were performed to analyze the independent effects of spexin on prevalence of DPN and painful DPN. In streptozotocin (STZ)‐induced diabetic mice, mechanical pain threshold was measured using electronic von Frey aesthesiometer. Human peripheral blood mononuclear cells (PBMCs) were isolated and further stimulated with lipopolysaccharide without or with spexin. The gene expression was assayed by qPCR.Results: Compared with non‐DPN, serum spexin level decreased in painless DPN and further decreased in painful DPN. The odds of DPN was associated with low spexin level in T2DM, which was similar by age, sex, BMI, and diabetes duration, but attenuated in smokers. The odds of having pain was associated with decreased spexin level in DPN, which was similar by age, sex, smoking status, and diabetes duration, but attenuated in normal weight. Furthermore, we observed that mechanical pain threshold increased in spexin‐treated diabetic mice. We also found that lipopolysaccharide treatment increased the mRNA level of TNF‐α, IL‐6, and MCP‐1 in human PBMCs, while spexin treatment prevented this increase.Conclusions: These results suggested that spexin might serve as a protective factor for diabetes against neuropathology and pain‐related pathogenesis.

Endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is an evolutionarily conserved and multifunctional factor across species. We previously reported that Emc10 knockout (KO) leads to mouse male infertility. Emc10-null spermatozoa exhibit multiple aspects of dysfunction, including reduced sperm motility. Two subunits of a Na/K-ATPase, ATP1A4 and ATP1B3, are nearly absent in Emc10 KO spermatozoa. Here, two isoforms of EMC10 were characterized in the mouse testis and epididymis: the membrane-bound (mEMC10) and secreted (scEMC10) isoforms. We present evidence that mEMC10, rather than scEMC10, is required for cytoplasm sodium homeostasis by positively regulating ATP1B3 expression in germ cells. Intra-testis mEMC10 overexpression rescued the sperm motility defect caused by Emc10 KO, while exogenous recombinant scEMC10 protein could not improve the motility of spermatozoa from either Emc10 KO mouse or asthenospermic subjects. Clinically, there is a positive association between ATP1B3 and EMC10 protein levels in human spermatozoa, whereas no correlation was proven between seminal plasma scEMC10 levels and sperm motility. These results highlight the important role of the membrane-bound EMC10 isoform in maintaining cytoplasm sodium homeostasis and sperm motility. Based on the present results, the mEMC10-Na, K/ATPase α4β3 axis is proposed as a novel mechanism underlying the regulation of cytoplasmic sodium and sperm motility, and its components seem to have therapeutic potential for asthenospermia.