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Objective: Obesity and related diseases are becoming a growing risk for public health around the world due to the westernized lifestyle. Sema7A, an axonal guidance molecule, has been known to play a role in neurite growth, bone formation, and immune regulation. Whether Sema7A participates in obesity and metabolic diseases is unknown. As several SNPs in SEMA7A and its receptors were found to correlate with BMI and metabolic parameters in the human population, we investigated the potential role of Sema7A in obesity and hepatic steatosis., Methods: GWAS and GEPIA database was used to analyze SNPs in SEMA7A and the correlation of Sema7A expression with lipid metabolism related genes. Sema7A -/- mice and recombinant Sema7A (rSema7A) were used to study the role of Sema7A in HFD-induced obesity and hepatic steatosis. Adipose tissue-derived mesenchymal stem cells (ADSCs) were used to examine the role of Sema7A in adipogenesis, lipogenesis and downstream signaling., Results: Deletion of Sema7A aggravated HFD-induced obesity. Sema7A deletion enhanced adipogenesis in both subcutaneous and visceral ADSCs, while the addition of rSema7A inhibited adipogenesis of ADSCs and lipogenesis of differentiated mature adipocytes. Sema7A inhibits adipo/lipogenesis potentially through its receptor integrin β1 and downstream FAK signaling. Importantly, administration of rSema7A had protective effects against diet-induced obesity in mice. In addition, deletion of Sema7A led to increased hepatic steatosis and insulin resistance in mice., Conclusions: Our findings reveal a novel inhibitory role of Sema7A in obesity and hepatic steatosis, providing a potential new therapeutic target for obesity and metabolic diseases., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Sema4D, a member of the immune semaphorin family, plays crucial roles in the immune regulation, bone resorption and nervous system. It is also involved in angiogenesis and tumour progression. However, systemic studies on the correlation between Sema4D expression and the immune infiltration or clinical outcomes in tumours are still limited. Here, we analysed the landscape of Sema4D expression and its prognostic value in the cancer genome atlas pan-cancer as well as the correlation between Sema4D and immune cell infiltration by Tumour Immune Estimation Resource and Gene Expression Profiling interactive analysis online tools. Results showed that a higher Sema4D expression was significantly correlated with a favourable overall survival in diverse solid tumours including bladder cancer (Hazards Ratio (HR)=0.68, p  = .0095), kidney renal clear cell carcinoma (HR = 0.61, p  = .0016), melanoma (HR = 0.58, p  = 6.6e-05) and thymoma (HR = 0.1, p  = .011). Interestingly, Sema4D expression has positive correlation with various tumour infiltrating immune cells and immune cell biomarkers in these tumours. These results suggest that Sema4D could be a prospective biomarker for calculating hazard ratio of tumour patients and their tumour immune infiltration levels.

Semaphorins are a family originally identified as axonal guidance molecules. They are also involved in tumor growth, angiogenesis, immune regulation, as well as other biological and pathological processes. Recent studies have shown that semaphorins play a role in metabolic diseases including obesity, adipose inflammation, and diabetic complications, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic wound healing, and diabetic osteoporosis. Evidence provides mechanistic insights regarding the role of semaphorins in metabolic diseases by regulating adipogenesis, hypothalamic melanocortin circuit, immune responses, and angiogenesis. In this review, we summarize recent progress regarding the role of semaphorins in obesity, adipose inflammation, and diabetic complications.

Semaphorin 7A (Sema7A), a neural guidance cue, was recently identified to regulate atherosclerosis in mice. However, the clinical relevance of Sema7A with atherosclerotic diseases remains unknown. The aim of this study was to investigate the association between serum Sema7A and the risk of acute atherothrombotic stroke (AAS). We measured serum concentrations of Sema7A in 105 newly onset AAS cases and 105 age- and sex-matched controls, showing that median Sema7A level in AAS cases was over three times of that in controls (5.86 vs 1.66 ng/mL). Adjusted for hypertension, body mass index, fasting blood glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, current smoking and alcohol consumption, multivariate logistic regression showed that higher Sema7A was independently associated with the odds of AAS (OR = 6.40, 95% CI: 2.88-14.25). Each 1-standard deviation increase in Sema7A was associated with a threefold higher odds of AAS (OR = 3.42, 95% CI: 1.84-6.35). Importantly, adding Sema7A to a multivariate logistic model containing conventional cardiovascular risk factors improved the area under receiver operating characteristic curves from 0.831 to 0.891 for the association with AAS. In conclusion, elevated serum Sema7A is independently associated with the risk of AAS, suggesting that it may play a potential role in AAS., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Semaphorin 4D (Sema4D/CD100) is a 150-kDa transmembrane glycoprotein expressed by platelets and T-cells. When these cells are activated, Sema4D is cleaved proteolytically, generating a biologically active 120-kDa fragment (soluble Sema4D) capable of targeting receptors on platelets, B-cells, endothelial cells and tumor cells. However, its plasma levels and significance in heart failure (HF) have not been reported. In this study, we established an ELISA and detected soluble Sema4D in human plasma. In healthy controls, plasma Sema4D levels were higher in men than women (5.15±3.30 ng/mL, n = 63, vs. 4.19±2.39 ng/mL, n = 63, P<0.05). In HF patients, plasma Sema4D levels were significantly higher than those in healthy controls (8.94±5.89 ng/mL, n = 157 vs. 4.67±2.99 ng/mL, n = 126, P<0.0001) with the highest levels being in HF patients with diabetes mellitus (DM) (10.45±5.76 ng/mL, n = 40). We also found that there was a higher percentage of Sema4D(high) CD3(+) (P<0.01), CD4(+) (P<0.001), and CD8(+) (P<0.01) T-cells in samples from HF patients, but no changes in Sema4D expression levels in B cells and platelets. Therefore, our investigation shows that plasma Sema4D levels are increased in HF patients, especially in those who also have diabetes. There was an accompanying increase in the Sema4D(high) population of T-cells, suggesting a potential role of these T-cells in heart failure.