Tumor Necrosis Factor α and Glucocorticoid Synergistically Increase Leptin Production in Human Adipose Tissue: Role for p38 Mitogen-Activated Protein Kinase

Maria E. Trujillo, Mi-Jeong Lee, Sean Sullivan, Jianying Feng, Stephen H. Schneider, Andrew S. Greenberg, Susan K. Fried
2006 Journal of Clinical Endocrinology and Metabolism  
Context: TNF increases plasma leptin in humans in vivo, but previous studies showed it decreases leptin in vitro. Objective and Participants: The objective of this study was to determine the effect of TNF on leptin release from human adipose tissue (AT) from healthy subjects undergoing elective surgery or needle aspirations of AT at a university hospital. Design: Human omental and abdominal sc AT fragments from nonobese and obese subjects were placed in organ culture without or with TNF added
more » ... or with TNF added in the presence or absence of insulin and/or dexamethasone (dex; a synthetic glucocorticoid) for up to 2 d. Results: In the absence of hormones, culture with TNF decreased leptin release. In contrast, when added in the presence of dex, TNF increased secreted leptin and leptin mRNA abundance in AT from nonobese and obese subjects. The TNF ϩ dex-stimulated increase in leptin was associated with an increase in p38 MAPK activity and was totally blocked by p38 MAPK inhibitors. In contrast, inhibition of p38 MAPK only partially blocked the effect of TNF on IL-6 production. Culture of obese AT with either p38 or p44/42 MAPK inhibitors also blunted the spontaneous increase in media leptin that occurred from d 1-2 of culture in omental AT of obese subjects. Conclusion: Synergistic effects of increased local or systemic TNF in combination with glucocorticoids may contribute to increased leptin expression in response to stress, including infection and obesity. (J Clin Endocrinol Metab 91: 1484 -1490, 2006) Subjects and Methods Subjects AT samples were obtained from the Om and sc depots of morbidly obese subjects (body mass index, 50 Ϯ 2 kg/m 2 , n ϭ 21, all female) who underwent gastric bypass surgery. AT was also obtained from the abdominal sc depots of lean volunteers (body mass index, 24 Ϯ 0.4 kg/m 2 , n ϭ 4, two females, two males) via fat aspiration under local anesthesia (20) . Subjects enrolled in this study were nondiabetic (by medical history) and not taking steroids, ␤-blockers, or statins. Those taking antihypertensives or antidepressants were not excluded. There was no indication of carryover effects from subjects taking antidepressants on the effects of dexamethasone (dex) in cultured human AT. All subjects gave informed consent, and protocols were approved by the Institutional
doi:10.1210/jc.2005-1901 pmid:16403817 fatcat:y6rla2rz7nehpn3ds5u5wmqvme