Mechanisms and significance of brain glucose signaling in energy balance, glucose homeostasis, and food-induced reward

•A long-standing hypothesis that hypothalamic glucose sensing plays a major role has been difficult to demonstrate, but recent studies strongly support this hypothesis.•A role for hypothalamic glucose sensing in glucose homeostasis has been more recently proposed and has also been increasingly substantiated in the last two decades.•A role for hypothalamic glucose sensing in food-induced reward has even more recently been proposed, and while not definitely yet demonstrated recent studies have strongly supported this hypothesis.

The concept that hypothalamic glucose signaling plays an important role in regulating energy balance, e.g., as instantiated in the so-called “glucostat” hypothesis, is one of the oldest in the field of metabolism. However the mechanisms by which neurons in the hypothalamus sense glucose, and the function of glucose signaling in the brain, has been difficult to establish. Nevertheless recent studies probing mechanisms of glucose signaling have also strongly supported a role for glucose signaling in regulating energy balance, glucose homeostasis, and food-induced reward.