The brain histaminergic system plays a pivotal role in energy homeostasis, through H1-
receptor activation, it increases the hypothalamic release of histamine that decreases food intake and
reduces body weight. One way to increase the release of hypothalamic histamine is through the use of
antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors
located on the presynaptic membranes and cell soma of neurons, where they negatively regulate
the synthesis and release of histamine and other neurotransmitters in the central nervous system.
Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed,
conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal
studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on
the drug, spice, and route of administration, among others. The present review will explore the state of
art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a
brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation
of the histaminergic system in food intake and body weight, and the H3-receptor as a potential
therapeutic target for obesity.