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.
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Authors | Jing Wang, Leylla Badeanlou, Jacek Bielawski, Theodore P Ciaraldi, Fahumiya Samad |
Journal | American 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 |
PMID | 24473437
(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.)
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Chemical References |
- Inflammation Mediators
- Phosphotransferases (Alcohol Group Acceptor)
- sphingosine kinase
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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)
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