Proopiomelanocortin neurons have been primarily described as controlling feeding behavior, but accumulating evidence also showed a crucial role of these neurons in the control of glucose homeostasis. For this, and in addition of being able to sense peripheral signals, POMC neurons receive direct upstream excitatory (glutamate) and inhibitory (GABA) inputs coming from a plethora of brain areas. Remarkably, EphrinBs (EphrinB1, B2, B3) proteins are well-known actor of glutamatergic synapse formation and plasticity. A study from our group showed that the modulation of EphrinB1 a during development, led to reduced number of glutamatergic inputs into POMC neurons, impaired glutamatergic-dependent activity and insulin secretion in response to hyperglycemia. EphrinBs are still expressed in POMC neurons of adult mice, however we still do not know to which extend these three proteins could participate to the control of energy and glucose homeostasis through synaptic plasticity of POMC neurons. To determine the role of EphrinB3 in the control of synaptic plasticity of POMC neurons, we overexpress (Pomc-Efnb3-OE) Efnb3 (gene encoding EphrinB3) in POMC neurons of male adult mice by stereotactic viral infusion and exposed the animals to high fat diet (HFD), a potent modulator of synaptic plasticity of POMC neurons. Interestingly, Pomc-Efnb3-OE male mice showed altered AMPA-dependent sEPSC of POMC neurons and displayed greater body weight gain, associated with an increased fat mass, compared to control mice. Ultimately, this project aims to provide novel mechanisms underlying the control of energy and glucose homeostasis through the synaptic plasticity of POMC neurons, and subsequently their activity.