Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Keywords:

• adipose tissue
• apoptosis
• ceramide
• insulin
• islet of Langerhans
• lipotoxicity
• liver
• muscle
• obesity
• pancreatic β cells
• sphingolipids
• sphingosine-1-phosphate
• type 2 diabetes

Acknowledgments

The work was supported by Centre National de la Recherche Scientifique (CNRS to C.M), Agence Nationale de la Recherche (ANR-06-JCJC-0040 S1P-Diabetes to HLS; ANR 11 BSV1 03101-Crisalis to EH; ANR Lipobrain 11-BSV1-02101 to CM), INSERM, the Société Francophone du Diabète (CM), the Fondation pour la Recherche Médical (EH) and the IMIDIA consortium (CM). M Campana is supported by a doctoral fellowship from the CORDDIM. Lara Bellini is supported by a doctoral fellowship from IMIDIA. J Véret is supported by a post-doctoral fellowship from the University Paris Diderot. The authors apologize to those authors whose work could not be cited owing to space limitations. L Bellini and M Campana have equally contributed to this work.

Declaration of interest

The authors were supported by CNRS, ANR, SFD, INSERM, FRM, CORDDIM and the IMIDIA consortium. J Veret is supported by the University of Paris Diderot. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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