Abstract
OBJECTIVES: Soluble CD52 (sCD52) derived from activated CD4(+) T cells regulates T cell immunity under autoimmune conditions; however, its role in obesity-associated chronic inflammation and glucose metabolism remains unclear. Therefore, we herein investigated the significance of CD52 in obesity. METHODS: CD52-knockout mice (KO) and their wild-type littermates were fed a high-fat diet (HFD) for 12 weeks and analyzed. RESULTS: sCD52 preferentially suppressed chronic liver inflammation and protected against impaired glucose tolerance and metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity. No significant differences were observed in weight gain or energy metabolism in KO mice; however, glucose metabolism was impaired. A histological examination revealed more severe chronic inflammation and steatosis in KO mice, accompanied by changes in liver transcriptome profiles, but no significant differences in epididymal white adipose tissue (eWAT). In contrast, CD52 expression was significantly up-regulated in eWAT, with slightly higher levels in the liver and skeletal muscle in HFD-fed obese C57BL/6 mice than in chow-fed controls. sCD52 was released from the cultured eWAT of obese mice, but not lean mice, and circulating sCD52 levels were higher in obese mice. A re-analysis of a public single-nucleus RNA sequencing library revealed that increased CD52 in eWAT was linked to immune cells and adipocytes. T cell-derived purified sCD52 suppressed macrophage activation in vitro. In contrast, sCD52 was not secreted from 3T3-L1 adipocytes, although its protein levels increased with differentiation. CONCLUSIONS: T cell-derived sCD52 mitigates the obesity-associated development of MASLD and glucose intolerance in mice.