The lethal yellow (A(Y)/a) mouse has a defect in proopiomelanocortin (POMC) signaling in the brain that leads to obesity, and is resistant to the anorexigenic effects of the hormone leptin. It has been proposed that the weight-reducing effects of leptin are thus transmitted primarily by way of POMC neurons. However, the central effects of defective POMC signaling, and the absence of leptin, on weight gain in double-mutant lethal yellow (A(Y)/a) leptin-deficient (lep(ob)/lep(ob)) mice were shown to be independent and additive, Furthermore, deletion of the leptin gene restored leptin sensitivity to A(Y)/a mice. This result implies that in the A(Y)/a mouse, obesity is independent of leptin action, and resistance to leptin results from desensitization of leptin signaling.