Nature Medicine11, 199 - 205 (2005)
Published online: 16 January 2005; | doi:10.1038/nm1178
There is an Erratum (March 2005) associated with this Article.
Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity
Mark W Sleeman, Katherine E Wortley, Ka-Man V Lai, Lori C Gowen, Jennifer Kintner, William O Kline, Karen Garcia, Trevor N Stitt, George D Yancopoulos, Stanley J Wiegand
& David J Glass
Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, New York 10591-6707, USA.
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 Inppl1EX19-28-/- 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.
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