Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Ma, M. M.; Chen, J. L.; Wang, G. G.; Wang, H.; Lü, Yuan; Li, J. F.; Yi, Jae Kyo; Yuan, Ying; Zhang, Q. W.; Mi, Jingyi; Wang, L. Sh.; Duan, Haifeng; Wu, Chu Tse

doi:10.1007/s00125-006-0589-5

Cited by 63 publications

(67 citation statements)

References 45 publications

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“…Thus, an insulin-mimetic effect of S1P occurs in skeletal muscle as the pharmacological inhibition of Sphk1 diminishes insulin-mediated glucose uptake, while its overexpression mimics insulin action in vivo [34]. Moreover, S1P shares with insulin the ability to elicit the differentiation of myoblasts.…”

Section: Discussionmentioning

confidence: 99%

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

et al. 2013

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Aims/hypothesis Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance. Methods The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice. Results Palmitate induced an impressive formation of extraand intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P 2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P 2 , was not able to inhibit insulin signalling. Conclusions/interpretation These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P 2 receptor to impair insulin signalling. In particular, S1P 2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

et al. 2013

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“…In rat adipocytes, S1P increases lipolysis and suppresses insulin-induced leptin secretion, consistent with a role in promoting insulin resistance (18). However, Ma et al (24) showed that adenoviral-mediated expression of human SK1 in KK/Ay T2D diabetic mice (Ad-SPHK1) reduced blood glucose levels and improved insulin sensitivity. In this instance, the effect of SK1 gene delivery on the tissue distribution of ceramide in these mice was not reported.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance

Wang

Badeanlou

Bielawski

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

100

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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 TNF␣ 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 Ϫ/Ϫ 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. sphingosine kinase 1; sphingosine 1 phosphate; adipose inflammation; insulin resistance; adipogenesis THE ADIPOSE TISSUE LIES AT THE HEART of the metabolic syndrome, and growing evidence indicates that obesity-associated metabolic disease occurs because of dysregulation of metabolic, endocrine, and immune functions of the adipose tissue (14,19,28). Impaired adipogenesis due to nutritional overload causes lipid deposition in ectopic tissues, including liver, muscle, and pancreases, and disrupts normal metabolic function (14,20,45,47). Adipose inflammation driven by both adipocytes and infiltration and activation of adipose tissue macrophages (ATM) further disrupts normal adipose function and is linked to the development of insulin resistance/type 2 diabetes (T2D) (28,29). Understanding the mechanisms that maintain metabolically healthy adipocytes and limit chronic adipose inflammation may identify novel targets for the treatment of obesityrelated metabolic complications.The bioactive sphingolipid sphingosine 1 phosphate (S1P) regulates signaling pathways crucial to cell growth, survival, migration, immune cell trafficking, angiogenesis, and inflammation (25,41,42). S1P is generated by phosphorylation of the ceramide metabolite sphingosine by two sphingosine kinases (SK1, SK2). S1P is synthesized by most cells, including platelets, erythrocytes, endothelial cells, mast cells, and macrophages (25, 41, 42). The major cellular and secreted source of S1P is derived from SK1 and mediates its functions through five cell-surface GPCRs (S1P1-5) or poorly defined intracellular targets (25,41,42). S...

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“…Recent studies suggest that such a rheostat may also exist for metabolic regulation. In stark contrast to ceramide, S1P promotes nutrient uptake (63) and increases basal and insulin-stimulated glucose uptake (64,65). The molecule has been shown to activate Akt/PKB in a wide variety of cell types (45,66,67).…”

Section: Figurementioning

confidence: 99%

Ceramides as modulators of cellular and whole-body metabolism

Bikman¹,

Summers²

2011

J. Clin. Invest.

362

297

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Nearly all stress stimuli (e.g., inflammatory cytokines, glucocorticoids, chemotherapeutics, etc.) induce sphingolipid synthesis, leading to the accumulation of ceramides and ceramide metabolites. While the role of these lipids in the regulation of cell growth and death has been studied extensively, recent studies suggest that a primary consequence of ceramide accumulation is an alteration in metabolism. In both cell-autonomous systems and complex organisms, ceramides modify intracellular signaling pathways to slow anabolism, ensuring that catabolism ensues. These ceramide actions have important implications for diseases associated with obesity, such as diabetes and cardiovascular disease. Conflict of interest:The authors have declared that no conflict of interest exists.Citation for this article:

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Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Cited by 63 publications

References 45 publications

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance

Ceramides as modulators of cellular and whole-body metabolism

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