UP-REGULATION OF ADIPOCYTE METABOLISM BY AGOUTI PROTEIN - POSSIBLE PARACRINE ACTIONS IN YELLOW MOUSE OBESITY

Mutations leading to ectopic expression of the murine agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo fatty a cid synthesis and desaturation, respectively. FAS and SCD mRNA in both tissues of obese (A(vy)) mice were dramatically increased relative to lean (a/a) controls. Excessive expression of these genes in this mode l could be due to direct effects of the agouti gene product; to test t his possibility we treated 3T3-L1 adipocytes in vitro with recombinant agouti protein. Agouti treatment increased FAS and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition, FAS activity and triglyce ride content were 3-fold higher in agouti-treated 3T3-L1 cells relativ e to controls; these effects were attenuated by simultaneous treatment with a calcium channel blocker (nitrendipine). These data demonstrate that the agouti protein can directly increase lipogenesis in adipocyt es and suggest that these effects are mediated through an intracellula r calcium-dependent mechanism.