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

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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Figure 1: Adipocyte-specific expression of the caspase 8–FKBP transgene in vitro and in vivo.
Figure 2: Dimerizer treatment in FAT-ATTAC animals results in adipocyte apoptosis and reversible loss of adipocyte-specific markers in vivo.
Figure 3: Effects of acute lipoatrophy in the FAT-ATTAC ob/ob mouse model.
Figure 4: Defects in insulin secretion in FAT-ATTAC mice.
Figure 5: Functional adipose is required for normal basal and LPS-stimulated inflammatory tone.

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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

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  1. Utpal B Pajvani
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Correspondence to Philipp E Scherer.

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Supplementary information

Supplementary Fig. 1

Higher magnification image of immunohistochemistry for F4/80 and perilipin antigens in residual adipose depot from 28 d AP20187-treated FAT-ATTAC mice. (PDF 234 kb)

Supplementary Fig. 2

Fatless FAT-ATTAC mice in the FVB background show no evidence of hepatic steatosis. (PDF 72 kb)

Supplementary Fig. 3

Decreased serum adipokines, increased MCP-1 in AP20187-treated FAT-ATTAC ob/ob animals. (PDF 59 kb)

Supplementary Fig. 4

Thiazolidinedione treatment results in improved hypertriglyceridemia, but minimal effects on hyperglycemia or hyperinsulinemia in lipoatrophic FAT-ATTAC mice. (PDF 60 kb)

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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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