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Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity

An Erratum to this article was published on 01 March 2005


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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Figure 1: Confirmation of deletion of endogenous SHIP2.
Figure 3: Phenotypic analysis of Inppl1−/− does not indicate impaired glucose homeostasis.
Figure 2: Analysis of LacZ reporter gene expression in Inppl1−/− mice.
Figure 4: Analysis of insulin signaling in Inppl1−/− mice.
Figure 5: SHIP2 deletion protects mice from diet-induced obesity and insulin resistance.

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We thank L.S. Schleifer and P.R. Vagelos for support, along with the rest of the Regeneron community, and are greatly indebted to our colleagues at Procter & Gamble Pharmaceuticals for their continued support; we also thank B. Ephraim and V. Lan for graphics work, A. Steuernagel for discussions and L. Suva for X-ray analysis. Thank you also to T. Dechiara, W. Poueymirou and M. Simmons for the coordinated breeding of knockout mice.

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Correspondence to David J Glass.

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The authors are stockholders in Regeneron Pharmaceuticals, which could receive financial gains as a result of this publication.

Supplementary information

Supplementary Fig. 1

Gene targeting of the SHIP2 locus. (PDF 60 kb)

Supplementary Fig. 2

Facial and X-ray analysis of SHIP2−/− mice did not reveal any gross abnormality. (PDF 96 kb)

Supplementary Fig. 3

SHIP2 deletion protects female mice from diet-induced obesity and insulin resistance. (PDF 111 kb)

Supplementary Fig. 4

Additional analysis of insulin signaling of SHIP2−/− mice, both on regular chow and on a high fat diet. (PDF 352 kb)

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Sleeman, M., Wortley, K., Lai, KM. et al. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Nat Med 11, 199–205 (2005).

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