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Reversal of obesity by targeted ablation of adipose tissue

Nature Medicine volume 10, pages 625–632 (2004)Cite this article

Abstract

Obesity is an increasingly prevalent human condition in developed societies. Despite major progress in the understanding of the molecular mechanisms leading to obesity, no safe and effective treatment has yet been found. Here, we report an antiobesity therapy based on targeted induction of apoptosis in the vasculature of adipose tissue. We used in vivo phage display to isolate a peptide motif (sequence CKGGRAKDC) that homes to white fat vasculature. We show that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and establish prohibitin as a vascular marker of adipose tissue. Targeting a proapoptotic peptide to prohibitin in the adipose vasculature caused ablation of white fat. Resorption of established white adipose tissue and normalization of metabolism resulted in rapid obesity reversal without detectable adverse effects. Because prohibitin is also expressed in blood vessels of human white fat, this work may lead to the development of targeted drugs for treatment of obese patients.

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Figure 1: In vivo fat homing of the CKGGRAKDC motif in genetically obese mice.
Figure 2: In vivo fat homing of the CKGGRAKDC motif in wild-type mice.
Figure 3: Physiological effects of treatment with CKGGRAKDC-GG-D(KLAKLAK)2.
Figure 4: Destruction of fat blood vessels as a result of targeted apoptosis.
Figure 5: Metabolism changes in obese mice in response to white fat ablation.
Figure 6: Prohibitin is the target of CKGGRAKDC in white fat.

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Acknowledgements

We thank E. Koivunen, P. Dougherty, J. Cordella, S. Craig and C.D. Bucana for technical assistance; J. Folkman, H. Sage and J. Licinio for critical reading of the manuscript; and J. Trent, R. Benjamin, R.E. Pollock, J. Hannay, G. Fusaro and S. Chellappan for reagents. This work was supported by grants from the NIH (CA88106, CA078512, CA90270 and CA82976 to R.P.; CA103042, CA90270 and CA90810 to W.A.; HL51586 to L.C.), and awards from the AngelWorks, the Gilson-Longenbaugh Foundation, Juvenile Diabetes Research Foundation and the V Foundation (R.P. and W.A.). M.G.K. is the recipient of a fellowship from the Susan G. Komen Breast Cancer Foundation (BC996405). L.C. is also supported by the Betty Rutherford Chair for Diabetes Research from St. Luke's Episcopal Hospital and Baylor College of Medicine.

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  1. Renata Pasqualini and Wadih Arap: These authors contributed equally to this work.

Authors and Affiliations

  1. The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Mikhail G Kolonin, Renata Pasqualini & Wadih Arap

  2. Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Pradip K Saha & Lawrence Chan

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  1. Mikhail G Kolonin
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Correspondence to Renata Pasqualini or Wadih Arap.

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The University of Texas and researchers (M.G.K., R.P. and W.A.) have equity and royalty in NTTX Biotechnology, which is subjected to certain limitations and restrictions under university policy; the university manages the terms of these arrangements in accordance with its conflict-of-interest policies.

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Kolonin, M., Saha, P., Chan, L. et al. Reversal of obesity by targeted ablation of adipose tissue. Nat Med 10, 625–632 (2004). https://doi.org/10.1038/nm1048

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