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

Department of Nutritional Sciences (M.E.T., M.-J.L., S.S., S.K.F.), Rutgers University and Division of Endocrinology (S.H.S.), University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08901; Jean Mayer U.S. Department of Agriculture, Human Nutrition Research Center on Aging (A.S.G.), Tufts University, Boston, Massachusetts 02111; and Division of Endocrinology, Diabetes, and Nutrition (M.-J.L., J.F., S.K.F.), Department of Medicine, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Susan K. Fried, Ph.D., Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, 660 West Redwood Street, Howard Hall 428, Baltimore, Maryland 21201. E-mail: sfried{at}medicine.umaryland.edu.

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 non- obese and obese subjects were placed in organ culture without 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 + 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.

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