Leptin and neuropeptide Y (NPY) dependent pathways from the hypothalamus have marked control over osteoblast activity. In cancellous bone, leptin-deficit (ob/ob) mice have increased anabolism, via β-adrenergic signaling. However, cortical bone mass is reduced, despite their obesity, although the mechanism for this effect is unknown. Hypothalamic NPY has a generalized anti-osteogenic effect, also reducing cortical bone mass, while significantly increasing weight (Baldock PA et. al. (2005) J Bone Miner Res. 20:1851–1857). Moreover, in the hypothalamus, leptin and NPY are inversely regulated, with increased NPY expression in ob/ob mice. We hypothesize that the reduced cortical bone mass of ob/ob mice is the result of NPY mediated processes. Femoral osteoblast activity of 16week,male ob/ob and NPY deficient ob/obmice (NPY/ob)wasexamined inbothcortical andcancellousbone. Body weight was significantly reduced in NPY/ob compared to ob/ob mice (45.3±1.2 vs 50.2±2.0 g, p<0.05), although femoral length was unchanged (16.0±0.1 vs 15.5±0.2 mm). Bone formation was greater in NPY/ob mice at the mid-shaft on both periosteal (1.36±0.10 vs 0.91±0.10 μm/d, p<0.01) and endosteal surfaces (1.39±0.18 vs 0.35±0.22 μm/d, p<0.005). Despite the magnitude of the periosteal effect (1.5-fold), mid femoral cortical dimensions were not different between genotypes, indicating a late-onset effect. In cancellous bone, there were no additive effects of leptin and NPY deficiency in cancellous bone volume (14.1±0.9 vs 14.7±1.5%) and mineral apposition rate (1.66±0.06 vs 1.67±0.07 μm/d), consistent with previous reports (Baldock PA et.al (2006) J Bone Miner Res. 21:1600–1607). These data indicate that NPY plays an important role in modulation of cortical bone anabolism in ob/ob mice, and indicate for the first time a putative mechanism behind the opposing cortical and cancellous responses in this model. Given the relative abundance of cortical bone, the most prominent skeletal phenotype in ob/ob mice appears to be an NPY-mediated inhibition of cortical bone formation. (1) Baldock PA et. al. (2005) J Bone Miner Res. 20:1851–1857. (2) Baldock PA et.al (2006) J Bone Miner Res. 21:1600–1607.