Subcutaneous administration of the sphingosine kinase 2 inhibitor ABC294640 has no metabolic benefits in high fat diet-induced obesity in male mice

Experimental evidence suggests an important role for sphingosine-1-phosphate (S1P) and its generating enzymes sphingosine kinase 1/2 (SphK1/2) in obesity. We and others have shown that plasma S1P levels are elevated in obese mice and humans. Preclinical studies suggest that genetic SphK2 ablation in mice protects from age- and diet-induced obesity and metabolic dysfunction. We aimed at investigating the therapeutic potential of pharmacological SphK2 inhibition using a high-fat diet (HFD)-induced obesity model. Male C57BL/6J mice were fed either a HFD (60 % fat) or a nutrient-matched control diet (CD; 10 % fat) for 9 weeks. After 7 weeks of diet exposure, when HFD-fed mice exhibited increased weight gain, impaired glucose tolerance and reduced insulin sensitivity, mice were subjected to subcutaneous SphK2 inhibitor (SphK2i, ABC294640, 5 mg/kg) or vehicle treatment every second day for two weeks. SphK2 expression was upregulated in adipose and liver tissue in response to HFD. Despite this, SphK2 inhibition did not attenuate hepatic steatosis, reduce liver weight, or improve metabolic hepatic gene expression profiles. Moreover, SphK2 inhibition exacerbated certain HFD-induced impairments, including worsened insulin tolerance and increased adipocyte hypertrophy. In CD-fed mice, SphK2 inhibition altered adipocyte size distribution but had no significant impact on systemic metabolism. Contrary to prior studies, our findings reveal no therapeutic benefit of SphK2 inhibition in diet-induced obesity. These results underscore the importance of tissue and context specificity in targeting the sphingosine kinase pathway and caution against broadly applying SphK2 inhibition as a strategy for treating obesity-associated metabolic dysfunction.