Predicted secreted protein analysis reveals synaptogenic function of Clstn3 during WAT browning and BAT activation in mice

Shu-qin Chen1, Qiang Niu2, Li-ping Ju1, Miriayi Alimujiang1, Han Yan1, Ning-ning Bai1, Jun Xu3, Qi-chen Fang1, Jun-feng Han1, Ying Yang1, Wei-ping Jia1
1 Shanghai Key Laboratory of Diabetes, Shanghai Institute for Diabetes, Shanghai Clinical Medical Centre of Diabetes, Shanghai Key Clinical Centre of Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
2 National Engineering Research Center of Die and Mold CAD, Shanghai Jiao Tong University, Shanghai 200030, China
3 Department of Geriatrics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
Correspondence to: Jun-feng Han:, Ying Yang:,
DOI: 10.1038/s41401-019-0211-2
Received: 26 August 2018
Accepted: 5 January 2019
Advance online: 22 February 2019


Promoting white adipose tissue (WAT) browning and enhancing brown adipose tissue (BAT) activity are attractive therapeutic strategies for obesity and its metabolic complications. Targeting sympathetic innervation in WAT and BAT represents a promising therapeutic concept. However, there are few reports on extracellular microenvironment remodeling, especially changes in nerve terminal connections. Identifying the key molecules mediating the neuro-adipose synaptic junctions is a key point. In this study, we used bioinformatics methods to identify the differentially expressed predicted secreted genes (DEPSGs) during WAT browning and BAT activation. These DEPSGs largely reflect changes of cytokines, extracellular matrix remodeling, vascularization, and adipocyte-neuronal cross-talk. We then performed functional enrichment and cellular distribution specificity analyses. The upregulated and downregulated DEPDGs during WAT browning displayed a distinctive biological pattern and cellular distribution. We listed a cluster of adipocyte-enriched DEPSGs, which might participate in the cross-talk between mature adipocytes and other cells; then identified a synaptogenic adhesion molecule, Clstn3, as the top gene expressed enriched in both mature white and brown adipocytes. Using Q-PCR and immunohistochemistry, we found significantly increased Clstn3 expression level during WAT browning and BAT activation in mice subjected to cold exposure (4 °C). We further demonstrated that treatment with isoproterenol significantly increased Clstn3 and UCP1 expression in differentiated white and beige adipocytes in vitro. In conclusion, our study demonstrates that the secretion pattern was somewhat different between WAT browning and BAT activation. We reveal that Clstn3 may be a key gene mediating the neuro-adipose junction formation or remodeling in WAT browning and BAT activation process.
Keywords: WAT browning; BAT activation; Calsyntenin-3; neuro-adipose synapse; isoproterenol; obesity

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