Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy (original) (raw)

Nature Medicine volume 11, pages 797–803 (2005) Cite this article

Abstract

We describe the generation and characterization of the first inducible 'fatless' model system, the FAT-ATTAC mouse (fat apoptosis through targeted activation of caspase 8). This transgenic mouse develops identically to wild-type littermates. Apoptosis of adipocytes can be induced at any developmental stage by administration of a FK1012 analog leading to the dimerization of a membrane-bound, adipocyte-specific caspase 8–FKBP fusion protein. Within 2 weeks of dimerizer administration, FAT-ATTAC mice show near-knockout levels of circulating adipokines and markedly reduced levels of adipose tissue. FAT-ATTAC mice are glucose intolerant, have diminished basal and endotoxin-stimulated systemic inflammation, are less responsive to glucose-stimulated insulin secretion and show increased food intake independent of the effects of leptin. Most importantly, we show that functional adipocytes can be recovered upon cessation of treatment, allowing the study of adipogenesis in vivo, as well as a detailed examination of the importance of the adipocyte in the regulation of multiple physiological functions and pathological states.

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Acknowledgements

We would like to thank T. Schraw for his assistance in the preparation of this manuscript, D.S. Jayabalan and C. Latham for technical assistance for histology and immunohistochemistry, M. Surana in our DRTC assay core for adiponectin measurements, and M. Brownlee and R. Ahima for helpful discussions. We would like to thank Ariad Pharmaceuticals for providing the basic plasmid encoding the Phe36Val mutant FKBP and AP20187 dimerizer. This work was supported by US National Institutes of Health (NIH) Medical Scientist Training Grant T32-GM07288 (to U.B.P.), by a NIH National Research Service Award (DK61228, to T.P.C.), NIH grants R01-DK55758 (to M.E.T. and P.E.S.), RO3 EYO14935 (to P.E.S.) and 1R01HL073163-01 (to P.E.S. and L.J.). P.E.S. is also a recipient of an Irma T. Hirschl Career Scientist Award.

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Author notes

  1. Terry P Combs
    Present address: Department of Nutrition, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, CB7461, Chapel Hill, North Carolina, 27599–7461, USA
  2. Utpal B Pajvani and Maria E Trujillo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA
    Utpal B Pajvani, Maria E Trujillo, Terry P Combs, Puneeth Iyengar, Richard N Kitsis & Philipp E Scherer
  2. Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA
    Linda Jelicks
  3. Division of Neuropathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA
    Kevin A Roth
  4. Department of Medicine Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA
    Richard N Kitsis & Philipp E Scherer
  5. Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA
    Philipp E Scherer

Authors

  1. Utpal B Pajvani
  2. Maria E Trujillo
  3. Terry P Combs
  4. Puneeth Iyengar
  5. Linda Jelicks
  6. Kevin A Roth
  7. Richard N Kitsis
  8. Philipp E Scherer

Corresponding author

Correspondence toPhilipp E Scherer.

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Competing interests

The authors declare no competing financial interests.

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Pajvani, U., Trujillo, M., Combs, T. et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy.Nat Med 11, 797–803 (2005). https://doi.org/10.1038/nm1262

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