Obesity is a major global healthcare concern, with over 600 million adults worldwide currently classified as living with the condition1. Obesity has been linked to numerous comorbid conditions ranging from type 2 diabetes mellitus and cardiovascular disease to a high percentage of cancers2 . A core link between obesity and these comorbidities is chronic inflammation3 , and thus the quest to understand the initiators and drivers of this pathogenic process in people with obesity is critically important and may lead to future therapeutics. In this issue of Nature Immunology, Qiu and colleagues identify the transcription factor IRX3 as a key driver of pro-inflammatory cytokine production in macrophages, which in mouse models is associated with repression of lipolysis and thermogenesis, leading to increased bodyweight and poor metabolic health4.