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Bone marrow–specific Cap gene deletion protects against high-fat diet–induced insulin resistance

Nature Medicine volume 13, pages 455–462 (2007)Cite this article

Abstract

Cbl-associated protein (Cap) is a member of a phosphatidylinositol 3-kinase–independent pathway for insulin-stimulated translocation of the glucose transporter GLUT4. Despite this positive role of Cap in glucose uptake, here we show that deletion of the gene encoding Cap (official gene name: Sorbs1) protects against high-fat diet (HFD)–induced insulin resistance in mice while also having an opposite, insulin-sensitizing effect, accompanied by reduced tissue markers of inflammation. Given the emerging role of chronic inflammation in insulin resistance and the macrophage in initiating this inflammatory process, we considered that Sorbs1 deletion from macrophages may have resulted in the observed protection from HFD-induced insulin resistance. Using bone marrow transplantation to generate functional Sorbs1-null macrophages, we show that the insulin-sensitive phenotype can be transferred to wild-type mice by transplantation of Sorbs1-null bone marrow. These studies show that macrophages are an important cell type in the induction of insulin resistance and that Cap has a modulatory role in this function.

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Figure 1: Sorbs1 knockout strategy.
Figure 2: In vivo glucose homeostasis and insulin sensitivity.
Figure 3: Inflammatory changes after HFD.
Figure 4: Protection from insulin resistance is conferred by Sorbs1−/− macrophages.
Figure 5: Altered monocyte/macrophage function after deletion of Sorbs1.

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Acknowledgements

We thank K. Chien for donation of the Sorbs1−/− mouse, T. Tran for performing the metabolic cage studies and J. Juliano for the hepatic triglyceride content measurements. This study was funded in part by the University of California Discovery Program Project (bio03-10383, BioStar) with matching funds from Pfizer Incorporated. This work was also supported by the National Institutes of Health (grants DK 33651 to J.M.O. and DK 60591 to A.R.S.). J.M.O. is a consultant for Pfizer Incorporated.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Lisa A Lesniewski, Sarah E Hosch, Jaap G Neels, Carl de Luca & Jerrold M Olefsky

  2. Institute for Genetic Medicine, 2250 Alcazar Street, CSC 240, Los Angeles, 90033, California, USA

    Mohammad Pashmforoush

  3. Departments of Internal Medicine and Physiology, Life Sciences Institute, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Carey N Lumeng, Shian-Huey Chiang & Alan R Saltiel

  4. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Carey N Lumeng

  5. Department of Radiology, University of California at San Diego, San Diego, 92098, California, USA

    Miriam Scadeng

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  1. Lisa A Lesniewski
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Contributions

L.A.L. completed the GTT, ITT, clamp studies, histological analyses, peritoneal macrophage isolations, bone marrow transplantations, immunoblotting, data analysis and manuscript preparation as a member of J.M.O.'s laboratory. S.E.H. carried out immunoblotting, assisted with peritoneal macrophage isolations and performed the LPS stimulation experiments. J.G.N. assisted with bone marrow transplantations and clamp studies. C.d.L. performed real-time PCR, GTTs, ITTs and assisted with clamp studies. M.P. generated the Sorbs1−/− mouse strain while in K. Chien's laboratory. C.N.L. and S.-H.C., members of A.R.S.'s laboratory, performed studies examining Sorbs1 function in RAW macrophages and isolated adipocytes. S.-H.C. also provided immunoblots showing Cap protein deletion. M.S. performed MRI scanning and analysis.

Corresponding author

Correspondence to Jerrold M Olefsky.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

No differences in metabolism or body composition between Cap(+/+) and Cap(−/−). (PDF 191 kb)

Supplementary Table 1

Animal characteristics, insulin sensitivity and macrophage infiltration into adipose tissue in HFD fed mice following reverse BMT experiments. (PDF 51 kb)

Supplementary Methods (PDF 72 kb)

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Lesniewski, L., Hosch, S., Neels, J. et al. Bone marrow–specific Cap gene deletion protects against high-fat diet–induced insulin resistance. Nat Med 13, 455–462 (2007). https://doi.org/10.1038/nm1550

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