Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance.
Adipose dysfunction resulting from chronic inflammation and impaired adipogenesis has increasingly been recognized as a major contributor to obesity-mediated insulin resistance, but the molecular mechanisms that maintain healthy adipocytes and limit adipose inflammation remain unclear. Here, we used genetic and pharmacological approaches to delineate a novel role for sphingosine kinase 1 (SK1) in metabolic disorders associated with obesity. SK1 phosphorylates sphingosine to form sphingosine 1 phosphate (S1P), a bioactive sphingolipid with numerous roles in inflammation. SK1 mRNA expression was increased in adipose tissue of diet-induced obese (DIO) mice and obese type 2 diabetic humans. In DIO mice, SK1 deficiency increased markers of adipogenesis and adipose gene expression of the anti-inflammatory molecules IL-10 and adiponectin and reduced adipose tissue macrophage (ATM) recruitment and proinflammatory molecules TNFα and IL-6. These changes were associated with enhanced insulin signaling in adipose and muscle and improved systemic insulin sensitivity and glucose tolerance in SK1(-/-) mice. Specific pharmacological inhibition of SK1 in WT DIO mice also reduced adipocyte and ATM inflammation and improved overall glucose homeostasis. These data suggest that the SK1-S1P axis could be an attractive target for the development of treatments to ameliorate adipose inflammation and insulin resistance associated with obesity and type 2 diabetes.
Department of Cell Biology, Torrey Pines Institute for Molecular Studies, San Diego, California;
Jing
J
Wang
Leylla
L
Badeanlou
Jacek
J
Bielawski
Theodore P
TP
Ciaraldi
Fahumiya
F
Samad
D017667:Adipocytes / Q000276:immunology / Q000378:metabolism; D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000378:metabolism; D015434:Panniculitis / Q000150:complications / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D000099157:Sphingosine Kinase
D018836:Inflammation Mediators; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase
adipogenesis; adipose inflammation; insulin resistance; sphingosine 1 phosphate; sphingosine kinase 1