Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity.
Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2), was previously reported to induce severe insulin sensitivity, leading to early postnatal death. In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a. We report a new SHIP2 knockout (Inppl1(-/-)) targeted to the translation-initiating ATG, which is null for Inppl1 mRNA and protein. Inppl1(-/-) mice are viable, have normal glucose and insulin levels, and normal insulin and glucose tolerances. The Inppl1(-/-) mice are, however, highly resistant to weight gain when placed on a high-fat diet. These results suggest that inhibition of SHIP2 would be useful in the effort to ameliorate diet-induced obesity, but call into question a dominant role of SHIP2 in modulating glucose homeostasis.
Sleeman
Mark W
MW
Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, New York 10591-6707, USA.
Wortley
Katherine E
KE
Lai
Ka-Man V
KM
Gowen
Lori C
LC
Kintner
Jennifer
J
Kline
William O
WO
Garcia
Karen
K
Stitt
Trevor N
TN
Yancopoulos
George D
GD
Wiegand
Stanley J
SJ
Glass
David J
DJ
D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight; D004041:Dietary Fats / Q000378:metabolism*; D005091:Exons; D005260:Female; D017353:Gene Deletion; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D000072181:Inositol Polyphosphate 5-Phosphatases; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D010641:Phenotype; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution
D004041:Dietary Fats; D007328:Insulin; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606435:Inppl1 protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D005947:Glucose