We found that via stimulating mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in the neurites and increasing POMC neuronal firing rates and excitability, TNFα induces mitochondrial stress in POMC neurons that in long run, could contribute to POMC neuronal dysfunction in control of energy balance and eventually lead to obesity. Here, TNF is linked to obesity due to melanocortin 4 receptor deficiency.