Adipokine IL-11/IL-11Ra constrains sphingolipid metabolism to limit the thermogenic capacity of beige adipocytes

Adipocytes exhibit cellular plasticity by secreting pro-inflammatory cytokines in response to an energy excess. Here, we identify that interleukin (IL)-11 is robustly induced and secreted from adipocytes, especially beige adipocytes upon adrenergic stimulation. IL-11 inhibits adipocyte thermogenesis through binding to IL-11 receptor a (IL-11Ra) and serves as a “brake” to maintain energy homeostasis. Adipocyte-specific IL-11Ra-knockout mice exhibit enhanced whole-body energy consumption and improved glucose and lipid metabolism under a high-fat diet (HFD). Inhibition of IL-11/IL-11Ra signaling enhances sphingosine kinase 1 (Sphk1)-driven production of sphingosine-1-phosphate (S1P), thus remodeling intracellular calcium cycling in beige adipocytes. Notably, treatment with a designed peptide against IL-11Ra in obese mice effectively alleviates fat accumulation and obesity-associated disorders. Taken together, our study defines a physiological and noncanonical mechanism of beige adipocyte-derived IL-11 in energy metabolism, which may serve as a promising target for the treatment of obesity. • IL-11 is an adipokine whose secretion is triggered by energy stress • IL-11 serves as a brake to limit energy overconsumption via IL-11Ra • IL-11/IL-11Ra inhibits Sphk1 and thus S1P production in beige adipocytes • IL-11Ra deficiency enhances thermogenesis and mitigates obesity Liu et al. identify that beige adipocyte-derived IL-11 inhibits energy expenditure by remodeling sphingolipid metabolism via binding to IL-11Ra. Inhibition of IL-11/IL-11Ra signaling promotes Sphk1-driven production of S1P, enhances mitochondrial function, and contributes to systemic metabolic benefits.