Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

• Published in: Diabetologia 2013-08, Vol.56 (8), p.1792-1801
• Main Authors: Mejhert, N., Wilfling, F., Esteve, D., Galitzky, J., Pellegrinelli, V., Kolditz, C.-I., Viguerie, N., Tordjman, J., Näslund, E., Trayhurn, P., Lacasa, D., Dahlman, I., Stich, V., Lång, P., Langin, D., Bouloumié, A., Clément, K., Rydén, M.
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipokines - genetics; Adipokines - metabolism; Adipose Tissue, White - metabolism; Biological and medical sciences; Body fat; Cells, Cultured; Connective tissue; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology and metabolism; Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Extracellular matrix; Extracellular Matrix - metabolism; Fluorescent Antibody Technique; Gastrointestinal surgery; Growth factors; Human health and pathology; Human Physiology; Humans; Immunohistochemistry; Insulin resistance; Internal Medicine; Life Sciences; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Microscopy, Confocal; Morphology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Obesity; Proteins; Semaphorins - genetics; Semaphorins - metabolism; Tumors; Weight control
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-013-2931-z

Aims/hypothesis Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function. Methods Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes. Results We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMA IR ], and the rate constant for the insulin tolerance test [K ITT ]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of β-oxidation genes. This could in part be explained by the significant downregulation of its cognate receptors during adipogenesis. In contrast, in pre-adipocytes, SEMA3C increased the production/secretion of several ECM components (fibronectin, elastin and collagen I) and matricellular factors (connective tissue growth factor, IL6 and transforming growth factor-β1). Furthermore, the expression of SEMA3C in human WAT correlated positively with the degree of fibrosis in WAT. Conclusions/interpretation SEMA3C is a novel adipokine regulated by weight changes. The correlation with WAT hypertrophy and fibrosis in vivo, as well as its effects on ECM production in human pre-adipocytes in vitro, together suggest that SEMA3C constitutes an adipocyte-derived paracrine signal that influences ECM composition and may play a pathophysiological role in human WAT.