IN-VIVO AND IN-VITRO EVIDENCE FOR THE INVOLVEMENT OF TUMOR-NECROSIS-FACTOR-ALPHA IN THE INDUCTION OF LEPTIN BY LIPOPOLYSACCHARIDE

To examine the role of tumor necrosis factor-alpha (TNF alpha) in medi ating leptin secretion during an immunological challenge, we studied t he effects of lipopolysaccharide (LPS) and TNF alpha on leptin secreti on in endotoxin-sensitive C3H/HeOuJ (OuJ) mice, endotoxin-insensitive C3H/HeJ (HeJ) mice, and primary adipocytes cultured hom both. Intraper itoneal injection of LPS increased plasma concentrations of TNF alpha and leptin in OuJ mice, but not in HeJ mice, suggesting a causal relat ionship between the induction of TNF alpha and leptin. Consistent with this idea, ip injection of recombinant murine TNF alpha increased pla sma leptin in both OuJ and HeJ mice. To determine whether TNF alpha in duces leptin secretion by acting directly on fat cells, primary adipoc ytes from OuJ and HeJ mice were cultured in the presence of TNF alpha or LPS. Whereas LPS was without effect on leptin secretion by adipocyt es, TNF alpha induced a marked increase in the cell supernatant leptin concentration. These data demonstrate that TNF alpha plays a role in regulating the increase in leptin caused by LPS. Moreover, they show t hat TNF alpha can act directly on adipocytes to stimulates leptin secr etion. Our results are consistent with the emerging view that leptin i s a key hormone coupling immune system activity to energy balance.