Interferon alpha (IFN-alpha) is produced in response to viral infections and used clinically in the therapy of a variety of cancers and viral infections. IFN-a treatment is often associated with severe weight reduction. To elucidate the mechanism of IFN-associated weight loss, we Studied its effect on adipocytes in vitro and in vivo. Diet-induced obese (DIO) C57BL/6 mice were treated continuously for 8 days with human IFN-alpha A/D (100 U/g body weight) or with vehicle alone. The body weight and adipose cell size of IFN-alpha A/D-treated DIO mice were significantly lower (P < 0.05 and P < 0.001, respectively) as compared with those of control DIO mice. PI3K and Bcl-2 were down-regulated whereas Bax expression was elevated in adipose tissue following IFN treatment as compared to adipose tissue of control DIO mice. Treatment of differentiated 3T3-F442A adipocytes with IFN-alpha A/D (250 U/ml, 36 h) significantly increased the number of apoptotic cells from 15.8% in control cells to 56 +/- 6%. In conclusion, weight loss following IFN-alpha therapy is due at least in part to increased apoptosis of adipocytes. (c) 2006 Elsevier Inc. All rights reserved.