Obesity is a highly prevalent disease in the world and with a major impact on global health. While genetic components are also involved in its pathogenesis, in recent years, it has shown a critical role of the innate and adaptive immune cell response in many tissues triggered by excess of nutrients such as lipids and glucose. Free fatty acids and other nutrient-related signals induce damage such as insulin resistance in the peripheral tissues but also in the brain. Specifically in the hypothalamus, these metabolic signals can trigger significant changes in the control of energy balance. Recent studies have shown that saturated fat disrupts melanocortin signaling of hypothalamic neuronal subgroups pivotal to energy control. Bariatric surgery is a treatment option for obesity when other tools have failed, because it is more effective than pharmacotherapy concerning of weight loss itself and in improvement of obesity-related comorbidities. Here, we review the mechanisms by which Roux-en Y gastric bypass (RYGB) can change peripheral signals that modulate melanocortin circuits involved in the regulation of energy balance.