BACE1 (β-site amyloid precursor protein (APP)-cleaving enzyme 1) is the rate-limiting step in Aβ peptide production. Aβ aggregates and forms amyloid plaques, a major pathological feature of Alzheimer’s disease. Mice lacking BACE1 have improved glucose homeostasis and are resistant to diet induced obesity [1], suggesting that BACE1 regulates energy metabolism. Therefore we have investigated whether altered leptin signalling underlies the improved metabolic phenotype of BACE1-/- mice. Wild-type (WT) and BACE1-/- mice (C57Bl/6) were fed regular chow (RC) or high fat (HF; 4% and 45% energy from fat respectively) diet from 8 weeks of age for 20 weeks. For in vivo studies mice were injected i.p. twice daily with saline or leptin (2mg/kg) for 3 days and food intake and body weight monitored. For biochemical analysis, mice were starved overnight and injected i.p with saline or leptin (3mg/kg) and hypothalamic arcuate nucleus (ARC) tissue harvested after 3 hours. cDNA expression was measured using Taqman gene analysis. Standard immunohistochemical and immunoblotting techniques were used to measure BACE1 hypothalamic distribution and ARC STAT3 protein levels, respectively. All data expressed as mean ± SEM, and statistical significance determined by Student’s t-test. BACE1 protein was observed in a sub-group of ARC neurons. BACE1 is not co-localised with NPY or AgRP, whereas approximately 30% of POMC neurons display BACE1 immunoreactivity. BACE1-/- mice, on RC diet, exhibit an increased in vivo response to leptin displaying a greater reduction in body weight compared to WT mice (KO -7.8±1.0%; WT -5.2±0.4%; p < 0.05 n=8-13). This outcome is reflected in a greater increase in ARC STAT3 phosphorylation levels for BACE1-/- mice compared to WT controls (KO 6.7±1.2; WT 3.5±0.6 fold; p < 0.05 n=6-8). Following HF diet challenge, BACE1-/- mice retain leptin sensitivity, while WT mice become leptin resistant (body weight change: KO -5.9±0.8%; WT -0.3±0.4%; p < 0.001 n=7-9). BACE1-/- mice display increased basal AgRP and NPY gene expression (AgRP 1.6±0.1; NPY 2.3±0.4 fold; p < 0.05 n=7), while POMC mRNA levels are unaltered. To investigate the mechanism by which loss of BACE1 enhances leptin sensitivity we examined the expression of negative regulators of leptin signalling. PTP1B and SHIP2 mRNA levels are unaltered in BACE1-/- mice on either diet. Whereas SOCS3 mRNA expression is increased in WT, but not BACE1-/-, mice on HF diet (1.8±0.2 and -1.1±0.1 fold respectively; p < 0.05, n=7-8), correlating with STAT3 phosphorylation levels. Taken together these data indicate that BACE1 is a regulator of hypothalamic leptin sensitivity in mice. Consequently, BACE1 inhibition may be a novel therapeutic intervention to recover leptin sensitivity, reduce body weight and improve glucose homeostasis in people with obesity/Type 2 diabetes.