A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition

The adipose tissue includes various stromal cells, such as preadipocytes, endothelial cells, fibroblasts, and immune cells, which are involved in adipose tissue functions. We previously reported that, in obese mice, the sodium-glucose cotransporter 2 inhibitor ipragliflozin (Ipra) promoted the expansion of the epididymal adipose tissue (Epi) with increase of serum ketone body concentration. The Ipra-induced adipose tissue expansion did not deteriorate adipose inflammation, or systemic glucose/lipid metabolism, referred to as healthy adipose tissue expansion. Here we found that Ipra promoted healthy adipose tissue expansion with a reduced ratio of pro-inflammatory M1-like adipose tissue macrophages (ATMs) to anti-inflammatory M2-like ATMs. Ipra downregulated the gene expression of interleukin (IL)-15 (Il15) in stromal cells of Epi. IL-15 inhibited lipogenesis in 3T3-L1 cells associated with downregulation of the lipogenic gene. Ketone body beta-hydroxybutyrate suppressed Il15 gene induction in M1-polarized cultured macrophages, and a ketogenic diet reproduced the adipose tissue expansion without deteriorating systemic glucose metabolism in mice. Our data indicate that the phenotypic switch of ATMs could mediate healthy adipose tissue expansion by treatment with Ipra, and it may offer new insights into the pathophysiological mechanisms of adipose tissue expansion.