Previously, we revealed the dual enhancing effect of netoglitazone, an agonist of the peroxisome proliferator-activated receptor γ, on adipogenesis and osteoblastogenesis, and reported that fatty acid synthase (FASN) knockdown selectively repressed its pro-adipogenic effect. Here, we examined if a FASN inhibitor, C75, could selectively repress the pro-adipogenic effect of netoglitazone. Surprisingly, C75 promoted the adipogenic differentiation of multipotent C3H10T1/2 cells but inhibited 3T3-L1 preadipocytes. By identifying glycogen synthase kinase-3β and intracellular cAMP levels as regulatory targets of C75, we ultimately found the differential expression of adenosine receptor 3 (AR3) and AR2a on these cells. Inhibition of AR3 on C3H10T1/2 and AR2a on 3T3-L1 inhibited the effects of C75 on the differentiation of these cells. Our findings imply that cell-type-specific AR expression might account for the differential adipogenic effects of C75.
