title: Laforin, a dual specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice.
abstract: Laforin is a dual specificity protein phosphatase involved in Lafora disease (LD), a fatal form of progressive myoclonus epilepsy characterized by neurodegeneration and the presence of intracellular polyglucosan inclusions (Lafora bodies) in different tissues. In this work, we describe that mice lacking laforin (epm2a-/-) have enhanced insulin response leading to altered whole-body energy balance. This enhanced insulin response overactivates the Akt pathway which increases glucose uptake in the heart, resulting in increased glycogen levels and the formation of polyglucosan inclusions. In addition, enhanced insulin response resulted in increased liver lipid biosynthesis, resulting in hepatic steatosis. On the contrary, overexpression in rat hepatoma FTO2B cells of native laforin but not of a form lacking phosphatase activity (C266S) resulted in attenuation of insulin signaling. These results define laforin as a new regulator of insulin sensitivity, which provides novel insights into LD pathogenesis and identifies this phosphatase as a potential novel component of the insulin signaling cascade.
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC and Centro de Investigación Biomédica en Red de Enfermedades Raras, Jaime Roig 11, Valencia, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vernia
authors.forename: Miguel
authors.initials: M
authors.lastname: Heredia
authors.forename: Olga
authors.initials: O
authors.lastname: Criado
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez de Cordoba
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Garcia-Roves
authors.forename: Céline
authors.initials: C
authors.lastname: Cansell
authors.forename: Raphael
authors.initials: R
authors.lastname: Denis
authors.forename: Serge
authors.initials: S
authors.lastname: Luquet
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferre
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D020192:Lafora Disease / Q000201:enzymology* / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D051381:Rats; D015398:Signal Transduction / Q000235:genetics
chemical_list: D007328:Insulin; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D005947:Glucose