Although epidemiological studies have linked adipose inflammation with obesity, the underlying mechanisms are incomplete. It is widely accepted that the interaction between insulin target cells and pro-inflammatory cytokines from accumulated macrophages is a cause of insulin resistance. Reduced mitochondrial capacity has been confirmed in patients with type 2 diabetes, and generally disposes macrophages toward a pro-inflammatory phenotype. However, little is known about decreased mitochondrial function and its effects on secreted macrophage factors which regulate macrophage polarization.
Design and method:
To find out the soluble factors of macrophages in adipose inflammation, we have sought six transcriptomes from control macrophages and macrophages that were treated with rosiglitazone. We identified a secretory factor, GDF15, which is required for increased oxidative metabolism in M2-like macrophages stimulated with IL-4 and the PPARγ agonist, rosiglitazone.
Administration of GDF15 increased the oxidative function of macrophages, leading to their polarization into an M2-like phenotype, and reversed insulin resistance in ob/ob mice and in HFD-fed mice harboring myeloid-specific deletion of Crif1.
Reintroduction of GDF15-null macrophages into HFD-fed mice in which macrophages were depleted with clodronate treatment rendered them glucose intolerant. Moreover, GDF15 deficiency prevented improvement of insulin sensitivity in mice treated with the Th2 cytokine IL-4.
Thus, GDF15 is an important microenvironmental factor regulating phenotypic polarization of macrophages linked to improvement of systemic insulin resistance.