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.