MIC-1, a divergent member of the transforming growth factor-β superfamily⁽Reference Bootcov, Bauskin and Valenzuela¹⁾, is involved in the control of multiple cellular functions. Recently, MIC-1 has been implicated as a cachexia mediator inducing weight loss through the inhibition of appetite⁽Reference Johnen, Lin and Kuffner²⁾. Adipose tissue as an endocrine organ secretes proteins (adipokines), which modulate appetite, nutrient metabolism, insulin sensitivity, stress responses and inflammation⁽Reference Trayhurn and Bing³⁾. Given the diverse roles of MIC-1, adipose tissue could be important in the physiological function of this factor. The aim of the present study was therefore to examine whether MIC-1 is expressed in adipose tissue and whether it is a secretory product of adipocytes. The study also investigated factors that modulate MIC-1 production and the potential role of MIC-1 in adipocytes.

Mouse adipose tissues were collected from different depots of C57Bl/6 mice. Adipose tissue (visceral and subcutaneous) was also collected from human subjects with a wide range of BMI, undergoing general or bariatric surgery. For in vitro studies 3T3-L1 preadipocytes and human preadipocytes (Zen-Bio) were used and induced to differentiate into adipocytes in cell culture.

MIC-1 mRNA was detected in the major mouse adipose tissue depots (epididymal, perirenal, subcutaneous). In these depots MIC-1 gene expression was evident in both isolated mature adipocytes and stromal vascular cells. In 3T3-L1 adipocytes MIC-1 mRNA was detected before and after differentiation. Administration of leptin and IL-1β led to a reduction in MIC-1 mRNA levels (both P<0.01). Treatment with H₂O₂ induced a dose-dependent increase in MIC-1 mRNA (P<0.01) while 15-deoxy-12,14-PGJ₂ (15d-PGJ₂) caused a marked up-regulation of MIC-1 transcripts (19-fold; P<0.001).

MIC-1 mRNA and protein secretion were evident in human preadipocytes as well as differentiated adipocytes. MIC-1 gene expression and protein secretion by human adipocytes were stimulated by H₂O₂ and 15d-PGJ₂ (all P<0.01). In addition, recombinant MIC-1 increased adiponectin secretion by differentiated human adipocytes. MIC-1 mRNA and protein were also observed in human subcutaneous and visceral fat. MIC-1 mRNA levels were positively correlated with adiponectin mRNA in both visceral (r 0.43, P<0.05, n 23) and subcutaneous (r 0.65, P<0.01, n 16) depots. Moreover, MIC-1 mRNA was negatively associated with BMI (r −0.53, P<0.01, visceral; r −0.56, P<0.05, subcutaneous) and body fat mass (r −0.47, P<0.05, visceral; r −0.49, P<0.05, subcutaneous) in human subjects.

It is concluded that MIC-1 is expressed in adipose tissue and secreted from adipocytes and is therefore a new adipokine. Recombinant MIC-1 enhances adiponectin release, suggesting that it is a positive regulator of adiponectin. Taken together, MIC-1 as a novel adipokine may well have a paracrine role in the modulation of adipose tissue function and body fat mass.