AGOUTI MELANOCORTIN INTERACTIONS WITH LEPTIN PATHWAYS IN OBESITY/

The cloning of mouse obesity genes and their human homologues provides unique opportunities to identify novel cellular targets for therapeut ic intervention. The first of these to be cloned, agouti, antagonizes central nervous system melanocortin receptor (MCR) binding, resulting in hyperphagia and an obesity/hyperinsulinemia syndrome. There appears to be significant crosstalk between the agouti and leptin signaling s ystems. Agouti antagonism of central nervous system (CNS) MCR binding inhibits the anorexic effects of leptin; whereas agouti up-regulates a dipocyte leptin expression, serving to limit the magnitude of agouti-i nduced obesity. The effects of agouti and leptin mutations on obesity, however, are independent and additive. Agouti also regulates adipocyt e lipid metabolism, functioning both to increase the expression and ac tivity of lipogenic genes and to inhibit lipolysis. Both of these acti ons occur via a Ca2+-dependent mechanism, suggesting that modulation o f adipocyte Ca2+ transport may be a key target for further investigati on.