HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance.

Abstract
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.
AuthorsJing Wang, Leylla Badeanlou, Jacek Bielawski, Theodore P Ciaraldi, Fahumiya Samad
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 306 Issue 7 Pg. E756-68 (Apr 01 2014) ISSN: 1522-1555 [Electronic] United States
PMID24473437 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Inflammation Mediators
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
Topics
  • Adipocytes (immunology, metabolism)
  • Adipose Tissue (immunology, metabolism)
  • Adult
  • Aged
  • Animals
  • Case-Control Studies
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 (complications, metabolism)
  • Female
  • Humans
  • Inflammation Mediators (metabolism)
  • Insulin Resistance (genetics)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Obesity (complications, metabolism)
  • Panniculitis (complications, genetics, metabolism)
  • Phosphotransferases (Alcohol Group Acceptor) (physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: