To directly demonstrate the proobesity action of hypothalamic LepRb-neuron Slug, we generated Cre-dependent, neuron-specific AAV-hSyn-DIO-Slug vectors, and showed that MBH LepRb+ neuron–specific overexpression of Slug was sufficient to induce obesity, glucose intolerance, insulin resistance, and NAFLD in mice on a chow diet. Here, RIC8B is linked to obesity due to melanocortin 4 receptor deficiency.