title: Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes.
abstract: BACKGROUND
  Obesity is a major factor that is linked to the development of type 2 diabetes (T2D). Excess circulating fatty acids (FAs), which characterize obesity, induce insulin resistance, steatosis, β cells dysfunction and apoptosis. These deleterious effects have been defined as lipotoxicity.
  
  
  METHODS
  FAs are metabolized to different lipid species, including ceramides which play a crucial role in lipotoxicity. The action of ceramides on tissues, such as muscle, liver, adipose tissue and pancreatic β cells, during the development of T2D will also be reviewed. In addition, the potential antagonist action of other sphingolipids, namely sphingoid base phosphates, on lipotoxicity in skeletal muscle and β cells will be addressed.
  
  
  CONCLUSIONS
  Ceramide is a critical mediator to the development of T2D linked to obesity. Targeting proteins involved in ceramide's deleterious action has not been possible due to their involvement in many other intracellular signaling pathways. A possible means of counteracting ceramide action would be to prevent the accumulation of the specific ceramide species involved in both insulin resistance and β-cell apoptosis/dysfunction. Another possibility would be to adjust the dynamic balance between ceramide and sphingoid base phosphate, both known to display opposing properties on the development of T2D-linked obesity.
authors: Université PARIS-DIDEROT (7), Unité Biologie Fonctionnelle et Adaptative - UMR CNRS 8251, Équipe Régulation de la glycémie par le système nerveux central (REGLYS) , 4, rue Marie-Andrée Lagroua Weill-Halle, 75205 PARIS Cedex 13 , France +01 57 27 77 97 ; +01 57 27 77 96 ; herve.le-stunff@univ-paris-diderot.fr.
authors: Lara
authors: L
authors: Bellini
authors: Mélanie
authors: M
authors: Campana
authors: Rana
authors: R
authors: Mahfouz
authors: Aurélie
authors: A
authors: Carlier
authors: Julien
authors: J
authors: Véret
authors: Christophe
authors: C
authors: Magnan
authors: Eric
authors: E
authors: Hajduch
authors: Hervé
authors: H
authors: Le Stunff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002518:Ceramides / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D009765:Obesity / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D015398:Signal Transduction / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: D002518:Ceramides; D005227:Fatty Acids; D013107:Sphingolipids
keywords: adipose tissue; apoptosis; ceramide; insulin; islet of Langerhans; lipotoxicity; liver; muscle; obesity; pancreatic β cells; sphingolipids; sphingosine-1-phosphate; type 2 diabetes