Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice

Caffeine, an antagonist of the adenosine receptor A₁R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A₁R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A₁R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A₁Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice.