OBJECTIVE—A functional polymorphism leucine 7 proline in the human neuropeptide Y (NPY) gene leading to increased NPY release from sympathetic nerves is associated with traits of metabolic syndrome. Although hypothalamic NPY neurons play an established role in promoting positive energy balance, the role of NPY colocalized with norepinephrine in sympathetic nervous system and brain noradrenergic neurons remains obscure. RESEARCH DESIGN AND METHODS—To clarify the role of NPY in noradrenergic neurons, we generated a transgenic mouse overexpressing NPY under dopamine–β-hydroxylase promoter and characterized the metabolic phenotype of the OE-NPYDβH mouse. RESULTS—NPY levels are increased by 1.3-fold in adrenal glands and 1.8-fold in the brainstem but not in the hypothalamus in OE-NPYDβH mice. They display increased white adipose tissue mass and cellularity and liver triglyceride accumulation without hyperphagia or increased body weight. Hyperinsulinemia and impaired glucose tolerance develop by the age of 6 months in the OE-NPYDβH mice. Furthermore, circulating ghrelin is significantly increased in comparison with wild-type mice. CONCLUSIONS—The present study shows that even a moderate increase in NPY levels in noradrenergic neurons leads to disturbances in glucose and lipid metabolism. The OE-NPYDβH mouse is an interesting new model to investigate the pathophysiology of some key components of the cluster of abnormalities characterizing the metabolic syndrome.