Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis

Abstract

Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3–14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance. Tang et al. reveal that macrophage-derived itaconate acts as a paracrine inhibitor of adipose tissue thermogenesis by blocking succinate uptake into brown adipose tissue.