Abstract Body (Do not enter title and authors here): Introduction: Obesity is associated with chronic inflammation in adipose tissue, leading to dysregulation of metabolic homeostasis and the development of insulin resistance. Recent studies have emphasized the crucial role of adipose-resident regulatory T (Treg) cells in suppressing adipose tissue inflammation and maintaining metabolic health. Thus, understanding the mechanisms that regulate the enrichment of adipose resident Treg cells is essential to improve adipose tissue function and systemic metabolic health.
Hypothesis: We hypothesized that ceramides which are nutrient signals known to reduce cellular function under nutrient excess might impair Treg cell function and proliferation and accounts for their reduced enrichment in adipose tissue of obese mice, leading to enhanced inflammation and metabolic dysfunctions.
Method: We employed pharmacological inhibition of ceramide biosynthesis in adult obese mice to assess its impact on Treg cell frequency. Additionally, we generated Treg cell specific serine palmitoyltransferase (Sptlc) gene loss- and gain-of-function mouse models to selectively modulate ceramide synthesis and evaluate effects on Treg cell abundance, function, and metabolic outcomes. In vitro analyses further examined ceramide-mediated effects on Treg cell function and metabolism.
Results: We found that obesity-induced reductions in adipose resident Treg cell numbers were linked to accumulation of ceramide in Treg cell compartment. Systemic inhibition of ceramide synthesis increased adipose resident Treg cells. Treg-specific deletion of Sptlc gene significantly increased Treg cell numbers and suppressive function. This intervention promoted energy expenditure, improved insulin sensitivity, and reduced hepatic steatosis and inflammation. Conversely, ceramide gain-of-function reduced Treg cell frequency in spleen and adipose tissue, and impaired metabolic homeostasis in lean mice. Mechanistically, we found that ceramide are necessary and sufficient to inhibit Foxp3 expression via inactivation of STAT5 and inhibit glucose and fatty acid uptake to reduce Treg proliferation and function.
Conclusion: Our findings suggest that ceramide acts as a key nutrient signal regulating Treg cell metabolism. This metabolic regulation by ceramides suppresses Treg cell numbers and functions, in turn enhancing inflammation and insulin resistance. Targeting Treg cell ceramides could be a therapeutic strategy to improve metabolic health.