Transgenic mice in which the protein symphilin-1 is expressed in brain neurons display increased food intake, body weight and body adiposity and develop hyperinsulinemia, hyperleptinemia and impaired glucose tolerance. Restriction of food availability to the levels consumed by nontransgenic mice prevents the appearance of these features. Symphilin-1 is highly expressed in hypothalamic nuclei involved in feeding regulation and is endogenously expressed in response to fasting. These findings show that synphilin-1 has a previously unrecognized role in the central regulation of energy balance.