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Whether nesfatin-1 modulates the differentiation and lipid metabolism of brown adipocytes remains unknown. In the present study, we found that nesfatin-1 mRNA and protein were detectable in isolated brown adipocytes and gradually decreased during differentiation (95% CI 0.6057 to 1.034, p\u2009=\u20090.0001). The decrease in nesfatin-1 was associated with a significant reduction in p-S6. Exposure to nesfatin-1 promoted differentiation of brown adipocytes as revealed by a significant increase in UCP1 mRNA (p\u2009=\u20090.03) and lipolysis-related ATGL mRNA (p\u2009=\u20090.04). Nesfatin-1 attenuated phosphorylation of S6K and S6 during brown adipocyte differentiation. Activation of mTOR by leucine or deletion of TSC1 decreased expression of brown adipocyte-related genes UCP1, UCP3, PGC1\u03b1 and PRDM16, as well as COX8B and ATP5B. Both leucine and TSC1 deletion blocked nesfatin-1-induced up-regulation of UCP1, PGC1\u03b1, COX8B and ATP5B in differentiated brown adipocytes. 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