Mesothelial cells maintain energy homeostasis in adipose tissue through the production of interleukin-18.

BACKGROUND

Mesothelial cells, which have long been regarded as an inert cell population, form a depot-specific mesothelium structure surrounding visceral adipose tissue. Although emerging evidence has elucidated the previously unrecognized functionality of mesothelial cells in adipose tissue, their role in metabolic regulation remains largely unknown.

METHODS

Single-cell transcriptomes of mesothelial cells obtained from human omental adipose tissues were analyzed to determine cellular secretory function. Primary mesothelial cells were isolated from epididymal white adipose tissue (eWAT) of male C57BL/6 mice to validate the single-cell data. Adeno-associated viruses (AAVs) were bilaterally injected into eWAT of C57BL/6 mice to evaluate the effect of mesothelial cell-derived interleukin-18 (IL-18) on adipose homeostasis. Co-culture assays and recombinant IL-18 were administered to determine the direct effect of mesothelial cell-derived IL-18 on adipocyte lipolysis.

RESULTS

Mesothelial cells were the dominant producers of IL-18 in visceral adipose tissues at steady state. Downregulation of IL-18 in eWAT by AAV injection reduced eWAT mass and adipocyte size, without changing basal metabolic rate or whole-body glucose homeostasis. Meanwhile, downregulation of IL-18 significantly increased adipose lipolysis and led to high levels of serum free fatty acids and glycerol. In vitro co-culture assays further showed that, mesothelial cell-derived IL-18 inhibited adipocyte lipolysis, and this effect was reversed by an IL-18 neutralizing antibody. Mechanistically, IL-18 suppressed adipocyte lipolysis by affecting the expression of hormone-sensitive lipase and adipose triglyceride lipase.

CONCLUSIONS

This study reveals a previously unrecognized role for mesothelial cell-derived IL-18 in preserving lipid stores, thereby highlighting a physiological function of mesothelial cells in the maintenance of adipose tissue energy homeostasis.