Obesity is a progressive, relapsing disease with few therapies. Diet and lifestyle interventions are effective but are often temporary and many individuals regain weight. High-fat diet increases the excitability of AgRP neurons, a critical neuronal population for the regulation of food intake and body weight. Here we investigate the plasticity of AgRP neurons and the impact of high-fat diet on modulation by synaptic input. We find that diet-induced hyperexcitability of AgRP neurons is not reversed by a lower-fat diet intervention. High-fat diet is associated with changes in the synaptic modulation of AgRP neurons, with a paradoxical increase in inhibitory input accompanied by a loss of GABA-mediated inhibition due to a depolarizing shift in the reversal potential of the GABA-evoked Cl- current. These findings reveal that high-fat diet leads to decoupling of intrinsic and synaptic excitability in AgRP neurons, such that hyperexcitability of AgRP neurons persists despite an increase in inhibitory input, revealing a mechanism for the difficulty in sustaining weight loss.
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