Since IKKβ/NF-κB inhibition in the CNS represents a potential target therapy to combat obesity and most anti-inflammatory therapies have limited direct effects on IKKβ/NF-κB and a limited capacity for concentration in the CNS, our study provides substantial evidence that physical activity could help to reorganize the set point of nutritional balance and therefore aid in counteracting the energy imbalance induced by overnutrition through the anti-inflammatory response in hypothalamic neurons. Here, IKBKB is linked to obesity due to melanocortin 4 receptor deficiency.