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High-fat diet induced loss of GABAergic inhibition decouples intrinsic and synaptic excitability in AgRP neurons

By Austin C. Korgan, Wei Wei, Sophie L.A. Martin, Catherine C. Kaczorowski, Laura G. Reinholdt

Posted 31 May 2021
bioRxiv DOI: 10.1101/2021.05.31.446473

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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