Identification of Macrophage Inhibitory Cytokine-1 in Adipose Tissue and Its Secretion as an Adipokine by Human Adipocytes

Abstract

Macrophage inhibitory cytokine-1 (MIC-1), a divergent member of the TGF-beta superfamily, is involved in the control of multiple cellular processes and mediates cachexia through the inhibition of appetite. Adipose tissue as an endocrine organ secretes proteins (adipokines) that regulate energy homeostasis and other cellular functions. This study investigated whether MIC-1 is expressed in adipose tissue and whether MIC-1 is a secretory product of adipocytes. Mouse and human adipose tissues were collected from different depots. 3T3-L1 preadipocytes and human preadipocytes were induced to differentiate into adipocytes in cell culture. MIC-1 mRNA was detected in the major mouse adipose depots (epididymal, perirenal, sc). 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. MIC-1 mRNA and protein secretion were evident in human preadipocytes as well as differentiated adipocytes. MIC-1 production by human adipocytes was stimulated by H(2)O(2) and 15d-prostaglandin J(2). In addition, recombinant MIC-1 increased adiponectin secretion by differentiated human adipocytes. MIC-1 mRNA and protein were also observed in human sc and visceral fat. MIC-1 mRNA levels were positively correlated with adiponectin mRNA. Moreover, MIC-1 mRNA was negatively associated with body mass index and body fat mass in human subjects. We conclude that MIC-1 is expressed in adipose tissue and secreted from adipocytes and is therefore a new adipokine. MIC-1 may have a paracrine role in the modulation of adipose tissue function and body fat mass.

Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet

“…Our results in a cross-sectional cohort of obese and lean women showed that MIC-1 is expressed in human adipose tissue with no significant difference between lean and obese subjects either in subcutaneous or in visceral adipose tissue. In agreement with the results of Ding et al (16), we found significantly lower expression of MIC-1 in visceral than in subcutaneous fat in both lean and obese groups. Furthermore, we showed a significant relationship of MIC-1 mRNA expression in both adipose depots with circulating triglycerides suggesting a possible paracrine role of MIC-1 in adipose tissue metabolism (16).…”

“…In agreement with the results of Ding et al (16), we found significantly lower expression of MIC-1 in visceral than in subcutaneous fat in both lean and obese groups. Furthermore, we showed a significant relationship of MIC-1 mRNA expression in both adipose depots with circulating triglycerides suggesting a possible paracrine role of MIC-1 in adipose tissue metabolism (16). Our findings also indicated that the differences in circulating MIC-1 levels between the lean and the obese do not originate from differences in production in adipose tissue.…”

“…The fact that circulating MIC-1 levels are increased in both cachectic cancer patients and patients with obesity despite opposite changes in body weight and BF content argues rather against a direct role for body weight and BF content per se in the regulation of circulating MIC-1 levels. In a recently published paper, Ding et al (16) demonstrated that MIC-1 mRNA expression was inversely related to BMI while in our group of patients we did not find such relationship. The reason for different findings between Ding's study and our data is not clear but it could have been due to different group of patients (different age range, combined population of males and females in Ding's study versus only female population in our study), concomitant medications or other reasons.…”

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

“…41 ZAG gene expression and ZAG protein have both been detected in isolated human fat cells, SGBS ZAG and adiposity C Bing et al (Simpson-Golabi-Behmel syndrome) human adipocyte cell strain 14 and human primary adipocytes (ZenBio). 42 Importantly, ZAG, which contains a secretory signal sequence, 18 is secreted into the culture medium by differentiated adipocytes. 14 Also importantly, the level of ZAG release by human adipocytes has recently been demonstrated to be comparable with that of adiponectin (which is one of the most abundant proteins in adipose tissue).…”

Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer

“…Another proposed mechanism of MIC-1-induced weight loss is through paracrine effects on adipocytes (Ding et al, 2009). Recombinant MIC-1 stimulates adiponectin secretion by human adipocytes, thus potentially negatively regulating body fat mass (Ding et al, 2009).…”