Inflammation is a biological response mounted by the immune system against dangerous assaults that threaten the integrity and normal physiology of an organism. During the past decades, cross-disciplinary research from immunology and endocrinology has much broadened this knowledge by demonstrating that chronic conditions of nutritional excess constitute an independent category of inflammatory activators, and the resulting chronic and low-grade inflammation is an important characteristic of overnutrition-induced diseases. A large body of research has demonstrated that these diseases are pathogenically associated with the local, negative actions of inflammation in peripheral tissues predominantly including the liver, muscle, and fat. In this research background, more recent research has advanced to a new level, with the important discoveries showing that overnutrition-induced inflammation occurs in the brain and thus plays a broad and leadership role in overnutrition-induced diseases. While much more research establishments are expected in this emerging and quickly expanding research, the appreciated understandings have been mainly based on proinflammatory IKKβ/NF-κB pathway and related molecules in the hypothalamus. In this chapter, the author focuses on describing IKKβ/NF-κB-induced neural inflammation in the context of overnutrition-induced metabolic inflammation and especially the central roles of this neural inflammation in the development of a spectrum of overnutrition-related diseases.