Dietary restriction (DR) extends life span and improves glucose metabolism in mammals. Recent studies have shown that DR stimulates the production of brain-derived neurotrophic factor (BDNF) in brain cells, which may mediate neuroprotective and neurogenic actions of DR. Other studies have suggested a role for central BDNF signaling in the regulation of glucose metabolism and body weight. BDNF heterozygous knockout (BDNF+/-) mice are obese and exhibit features of insulin resistance. We now report that an intermittent fasting DR regimen reverses several abnormal phenotypes of BDNF(+/-) mice including obesity, hyperphagia, and increased locomotor activity. DR increases BDNF levels in the brains of BDNF(+/-) mice to the level of wild-type mice fed ad libitum. BDNF(+/-) mice exhibit an insulin-resistance syndrome phenotype characterized by elevated levels of circulating glucose, insulin, and leptin; DR reduces levels of each of these three factors. DR normalizes blood glucose responses in glucose tolerance and insulin tolerance tests in the BDNF(+/-) mice. These findings suggest that BDNF is a major regulator of energy metabolism and that beneficial effects of DR on glucose metabolism are mediated, in part, by BDNF signaling. Dietary and pharmacological manipulations of BDNF signaling may prove useful in the prevention and treatment of obesity and insulin resistance syndrome-related diseases.