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Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice

Nature Genetics volume 26, pages 474–479 (2000)Cite this article

Abstract

Obesity is a disorder of energy balance1. Hormone-sensitive lipase (HSL) mediates the hydrolysis of triacylglycerol2, the major form of stored energy in the body. Perilipin (encoded by the gene Plin), an adipocyte protein, has been postulated to modulate HSL activity3,4,5. We show here that targeted disruption of Plin results in healthy mice that have constitutively activated fat-cell HSL. Plin−/− mice consume more food than control mice, but have normal body weight. They are much leaner and more muscular than controls, have 62% smaller white adipocytes, show elevated basal lipolysis that is resistant to β-adrenergic agonist stimulation, and are cold-sensitive except when fed. They are also resistant to diet-induced obesity. Breeding the Plin −/− alleles into Leprdb/db mice reverses the obesity by increasing the metabolic rate of the mice. Our results demonstrate a role for perilipin in reining in basal HSL activity and regulating lipolysis and energy balance; thus, agents that inactivate perilipin may prove useful as anti-obesity medications.

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Figure 1: Generation of Plin−/− mice.
Figure 2: Phenotypic effect of Plin inactivation on body weight, adipose depots, lipid contents and muscle mass.
Figure 3: Histology of adipose tissues.
Figure 4: Lipolysis in vitro and in vivo.
Figure 5: Cold sensitivity and oxygen consumption.
Figure 6: Plin−/− mice are resistant to diet-induced and genetic obesity.

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Acknowledgements

We thank M.A. Lasuncion, A. Martin-Hidalgo, D. Gomez-Coronado, C. Holm and J.A. Contreras for help and technical advice; P. Younan, J. Wei and E. Ezell for technical assistance; N. Butte, H. Mersmann and V. Nannegari for help with regard to energy expenditure and body composition assessments; and L. Loddeke for editorial assistance. This work was supported by National Institutes of Health grants (HL-51586, L.C.; ES-06676, D.G.), and in part by USDA/ARS Cooperative Agreement 58-6250-6001 (A.L.), and the Sealy and Smith Foundation (D.G.).

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Authors and Affiliations

  1. Departments of Molecular & Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas , USA

    Javier Martinez-Botas, John B. Anderson, Darin Tessier, Benny Hung-Junn Chang, Kuang-Hua Chen & Lawrence Chan

  2. United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston , Texas, USA

    Alexandre Lapillonne

  3. Marine Biomedical Institute and Department of Radiology, University of Texas Medical Branch, Galveston, Texas , USA

    Michael J. Quast

  4. the Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, Texas, USA

    David Gorenstein

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  1. Javier Martinez-Botas
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Correspondence to Lawrence Chan.

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Martinez-Botas, J., Anderson, J., Tessier, D. et al. Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice. Nat Genet 26, 474–479 (2000). https://doi.org/10.1038/82630

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