AUTOCRINE INHIBITION OF LEPTIN PRODUCTION BY TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) THROUGH TNF-ALPHA TYPE-I RECEPTOR IN-VITRO

The aim of this study was to find factors which regulate m-leptin secr etion during pregnancy. Mouse parametrial adipocytes from day 13 of pr egnancy were cultured with or without mouse placentallactogen (mPL)-I, mPL-II, or mouse tumor necrosis factor-alpha (mTNF-alpha) and mouse-l eptin (m-leptin) concentration in the medium was assessed by RIA. Up t o four days of mPL-I or mPL-II treatment did not affect m-leptin secre tion. However, mTNF-alpha, which is produced by adipocytes, significan tly inhibited m-leptin secretion in a dose-and time-dependent manner. Antibody to mTNF-alpha completely blocked the inhibitory effect of mTN F-alpha on m-leptin secretion. mTNF-alpha significantly inhibited the expression of m-leptin messenger RNA. Agonistic polyclonal antibody di rected against the mTNF-type-I receptor (mTNF-RI) significantly inhibi ted m-leptin secretion, but the anti-mTNF-RII antibody did not change m-leptin secretion. Moreover, human TNF-alpha (h-TNF-alpha) also inhib ited human-leptin (h-leptin) secretion by cultured human adipocytes co llected from the subcutaneous fat of pregnant women. These results sug gest that TNF-alpha, which is secreted by adipocytes, inhibits m-lepti n secretion through mTNF-RI and suggest the presence of an autocrine o r paracrine regulation of leptin secretion in human and mouse adipose tissue in vivo. (C) 1998 Academic Press.