INDEPENDENT AND ADDITIVE EFFECTS OF CENTRAL POMC AND LEPTIN PATHWAYS ON MURINE OBESITY

The lethal yellow (A(Y)/a) mouse has a defect in proopiomelanocortin ( POMC) signaling in the brain that leads to obesity, and is resistant t o the anorexigenic effects of the hormone leptin. It has been proposed that the weight-reducing effects of leptin are thus transmitted prima rily by way of POMC neurons. However, the central effects of defective POMC signaling, and the absence of leptin, on weight gain in double-m utant lethal yellow (A(Y)/a) leptin-deficient (lep(ob)/lep(ob)) mice w ere shown to be independent and additive, Furthermore, deletion of the leptin gene restored leptin sensitivity to A(Y)/a mice. This result i mplies that in the A(Y)/a mouse, obesity is independent of leptin acti on, and resistance to leptin results from desensitization of leptin si gnaling.