Obesity is a major problem worldwide that increases risk for a wide range of diseases, including diabetes and heart disease. As such, it is increasingly important to understand how excess adiposity can perturb normal metabolic functions. It is now clear that this disruption involves not only pathways controlling lipid and glucose homeostasis but also integration of metabolic and immune response pathways. Under conditions of nutritional excess, this integration can result in a metabolically driven, low-grade, chronic inflammatory state, referred to as “metaflammation,” that targets metabolically critical organs and tissues to adversely affect systemic homeostasis. Endoplasmic reticulum dysfunction is another important feature of chronic metabolic disease that is also linked to both metabolic and immune regulation. A thorough understanding of how these pathways intersect to maintain metabolic homeostasis, as well as how this integration is altered under conditions of nutrient excess, is important to fully understand, and subsequently treat, chronic metabolic diseases.