Cytokines, such as tumor necrosis factor (TNF) and interleukin-6, may contribute to the anorexia and cachexia of infection, cancer, and AIDS. The present study tests the hypothesis that endotoxin alters the expression of two key fat cell proteins, leptin and β3-adrenergic receptor (β3-AR), through a mechanism involving TNF-α. Increasing doses of Escherichia coli endotoxin (lipopolysaccharide, LPS) resulted in dose-dependent elevations of plasma leptin (maximal response ~7-fold, half-maximal effective dose of ~16 μg/100 g body wt) and white fat leptin mRNA in C3/HeOUJ mice. LPS also produced a large decrease in adipose tissue β3-AR mRNA and a parallel reduction in β-agonist-induced activation of adenylyl cyclase. Changes in plasma leptin and β3-AR mRNA were preceded by an approximately threefold increase in white fat TNF mRNA. TNF administration resulted in changes similar to those seen with LPS. We conclude that endotoxemia results in an induction of leptin mRNA and a decrease in β3-AR mRNA in adipose tissue, an effect that may be mediated by alterations in TNF-α.