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The MMP14–caveolin axis and its potential relevance for lipoedema

Abstract

Lipoedema is associated with widespread adipose tissue expansion, particularly in the proximal extremities. The mechanisms that drive the development of lipoedema are unclear. In this Perspective article, we propose a new model for the pathophysiology of lipoedema. We suggest that lipoedema is an oestrogen-dependent disorder of adipose tissue, which is triggered by a dysfunction of caveolin 1 (CAV1) and subsequent uncoupling of feedback mechanisms between CAV1, the matrix metalloproteinase MMP14 and oestrogen receptors. In addition, reduced CAV1 activity also leads to the activation of ERα and impaired regulation of the lymphatic system through the transcription factor prospero homeobox 1 (PROX1). The resulting upregulation of these factors could effectively explain the main known features of lipoedema, such as adipose hypertrophy, dysfunction of blood and lymphatic vessels, the overall oestrogen dependence and the associated sexual dimorphism, and the mechanical compliance of adipose tissue.

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Fig. 1: Mutual impact of MMP14, CAV1, PROX1 and oestrogen receptors in lipoedema.
Fig. 2: Cellular consequences of a disruption of the CAV1–MMP14 interaction.

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Acknowledgements

N.J. acknowledges the support of a postdoctoral fellowship from the Lipedema Foundation (LFA #18). P.E.S. acknowledges the support of NIH grants R01-DK55758, R01-DK099110, RC2-DK118620, P01-DK088761 and P01-AG051459, and is also supported by an unrestricted grant from the Novo Nordisk Research Foundation.

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Correspondence to Philipp E. Scherer.

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I.L.K. is the managing partner of Wellcomet GmbH. Wellcomet GmbH provided support in the form of salaries for I.L.K., but did not have any additional role in decision to publish or preparation of the manuscript. The commercial affiliation of I.L.K. with Wellcomet GmbH does not alter the adherence to all journal policies on sharing data and materials. The other authors declare no competing interests.

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Kruglikov, I.L., Joffin, N. & Scherer, P.E. The MMP14–caveolin axis and its potential relevance for lipoedema. Nat Rev Endocrinol 16, 669–674 (2020). https://doi.org/10.1038/s41574-020-0395-z

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