The mechanobiology of adipocytes: Role of the mechanosensitive ion channel Piezo1 in adipose tissue development and obesity-associated metabolic disorders – ADIPOPIEZO

The ADIPOPIEZO consortium comprises 3 partners with complementary skills, notably in molecular and cellular biology, integrative physiology and biophysics. We used different models of genetically modified mice that do not express Piezo1 in white adipocytes or their progenitor or in thermogenic adipocytes to study the role of Piezo1 in the pathological remodelling of white adipose tissue in obesity and in the thermogenic functions of brown and beige adipocytes. These mice were fed a high-fat diet to make them obese or treated with a pharmacological compound activating the thermogenic functions of brown and beige adipocytes. Finally, the cellular function of Piezo1 was studied using mouse and human thermogenic adipocyte cell lines and Piezo1 currents measured in adipocytes by patch-clamp.

In collaboration with the team of Pr. S. Offermanns (Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany), we have shown that Piezo1 expression is increased in the white adipose tissue of mice made obese by a high-fat diet and that Piezo1-mediated mechano-signalling in white adipocytes controls the production of an adipocyte hormone, FGF1, which limits the pathological expansion of white adipose tissue and improves the metabolic complications of obesity. In collaboration with the team of Prof. A Xu's (State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong), we have shown that Piezo1-mediated mechano-signalling in bone marrow mesenchymal stem cells promotes their differentiation into bone cells and limits their differentiation into adipocytes via the regulation of inflammatory mediators. Activation of Piezo1 in white adipocytes or bone marrow stem cells could therefore have beneficial effects on the metabolic complications of obesity or osteoporosis.

We have shown that Piezo1 expression is increased in the brown adipose tissue of obese mice or mice exposed to cold, as well as in a brown adipose cell line stimulated by a pharmacological agent that activates their thermogenic function. This increased expression requires activation of lipolysis, suggesting that fatty acids may control Piezo1 expression. We have shown that the absence of Piezo1 in brown and beige adipocytes leads to a reduction in body fat in mice fed a standard diet and partially protects them from obesity and its metabolic complications. This is associated with an increased expression of several genes controlling the thermogenic functions of these adipocytes. Thus, blocking Piezo1-mediated mechano-signalling in thermogenic adipocytes could increase the thermogenic functions of these adipocytes and limit the development of obesity.

In conclusion, the ADIPOPIEZO project has contributed to new insights into the role of mechanosignaling in adipocytes. This project suggests that pharmacological activators of Piezo1 could have beneficial effects on obesity and osteoporosis by targeting white adipocytes or stem cells, and that conversely pharmacological inhibitors of Piezo1 could enhance the thermogenic functions of brown/beige adipocytes with beneficial effects in terms of reducing fat mass and the development of obesity.

1. Wang S, Cao S, Arhatte M, Li D, Shi Y, Kurz S, Hu S, Wang L, Shao J, Atzberger A, Wang Z, Wang C, Zang W, Fleming I, Wettschureck N, Honoré E, Offermanns S. Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice. Nat Commun 2020 May 8;11(1):2303
2. Douguet D, Patel A, Xu A, Vanhoutte PM, Honoré E. Piezo Ion Channels in Cardiovascular Mechanobiology. Trends Pharmacol Sci 2019 Dec;40(12):956-970. (Revue)
3. Douguet D, Honoré E. Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels. Cell 2019 Oct 3;179(2):340-354

The anabolic white adipose tissues and the thermogenic brown and beige fat regulate energy balance and glucose/lipid homeostasis. The pathological expansion of white adipose tissues in obesity contributes to the development of metabolic diseases, such as type 2 diabetes. White adipose tissues expand by hypertrophy of preexisting adipocytes, as well as through the formation of new adipocytes by differentiation of adipose progenitor cells, increasing the number of adipocyte (hyperplasia). Adipocyte hypertrophy contributes to the development of the metabolic complications of obesity, whereas adipocyte hyperplasia is thought to be protective. Obesity is also associated with thermogenic brown/beige fat deficiency, while promotion of brown adipose tissue activity or induction of beige adipocytes in white adipose tissue (browning of white adipose tissue) counteracts the adverse metabolic effects of obesity. However, there are major gaps in our understanding of the factors and mechanisms that regulate the hypertrophy/hyperplasia balance of white adipocyte in obesity, as well as the formation/activity of thermogenic adipocytes. Therefore, identification of new molecular pathways modulating these biological processes would be of great interest for the treatment of obesity and associated metabolic diseases.
White and brown adipocytes, as well as adipose progenitors are becoming recognized as exquisitely mechanosensitive cells, but the molecular identity of the involved mechano-sensors remains poorly understood. Our preliminary findings indicate that Piezo1, a non-selective cationic mechanosensitive ion channel, is abundantly expressed in white and brown adipocytes, being responsible for remarkably large stretch-activated currents. Importantly, we found that conditional invalidation of Piezo1 in mature white adipocytes from obese mice exacerbates adipocyte hypertrophy, white adipose tissue inflammation and glucose intolerance. These findings suggest that Piezo1 in white adipocytes is necessary to limit hypertrophy in obesogenic conditions. In addition, our data suggest that Piezo1 in adipose progenitors plays a role in the formation/function of thermogenic adipocyte. Based on these comprehensive series of unpublished data, we hypothesize that Piezo1 opening in adipocytes or adipose progenitors constitute a new layer of control for the expansion/function of white and brown adipose tissues, impacting the development of obesity and its metabolic complications. Therefore, the global objective of the ADIPOPIEZO project is to explore the functional role of Piezo1 in the regulation of white adipocyte biology, white adipose tissue expansion and the formation/activity of thermogenic brown and beige/brite adipocytes. We will: 1) explore the impact of obesity on the regulation of Piezo1 expression/function in human and mouse adipose tissues; 2) investigate how adipose Piezo1 controls adipocyte hypertrophy upon obesity. We will take advantage of a mouse model allowing an adipocyte-specific invalidation of Piezo1, to study the role of this mechanosensitive ion channel in the storage of lipids within white adipocytes and in adipogenesis; and 3) investigate the impact of Piezo1 deficiency specifically in either adipocytes or adipose progenitors on white-to-beige conversion of fat cells, beige adipogenesis and brown adipose tissue function. This project will provide novel knowledges about the role played by the mechanosensitive Piezo1 channel in the regulation of white adipose tissues and in the function of thermogenic adipose tissues. We propose that exploring the mechanobiology of adipocytes and adipose tissues is an original and important question that will hopefully lead to the identification of novel therapeutic strategies to fight obesity and associated metabolic diseases.