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

To achieve the objectives of the project, the ADIPOPIEZO consortium includes 3 partners with complementary expertise, notably in molecular and cellular biology, integrative physiology and biophysics. Mice with inducible Piezo1 invalidation in adipocytes (adiponectin-CreERT2 x Piezo1lox/lox mice) will be used to evaluate in vivo the role of Piezo1 in the pathological remodeling of white adipose tissue during obesity and the conversion of mature white adipocytes to beige/brown adipocytes in response to modulation of sympathetic tone. In addition, mice with Piezo1 invalidation in adipose progenitors (PdgfRa-Cre x Piezo1lox/lox mice) will be used to evaluate in vivo the role of Piezo1 in brown adipogenesis. Mice with Piezo1 invalidation in brown and beige/brite thermogenic adipocytes (Ucp1-Cre x Piezo1lox/lox mice) will be used to assess the role of Piezo1 in the function of beige/brite adipocytes and of brown adipose tissue. Finally, the cell-autonomous function of Piezo1 will be explored using cultured mouse and human adipocytes and adipose tissue explants.

Aim 1: We show that when mice are at room temperature, Piezo1 mRNA is higher in subcutaneous adipose tissue and brown adipose tissue of mice fed a high-fat diet compared to mice fed a standard diet. Similar results were found in genetically obese ob/ob mice. When mice were maintained at thermoneutrality, Piezo1 mRNA levels were also higher in the subcutaneous white adipose tissue of mice fed a high-fat diet compared to mice fed a standard diet.

Aim 2: Our results identify a central feedback mechanism by which mature adipocytes via Piezo1 control adipogenesis during the development of obesity and suggest that Piezo1-mediated adipocyte mechanosignaling may be targeted to limit the metabolic complications of obesity. This work was published in Nature Communication (Wang S et al, Nat Comm 2020).

Aim 3: Our preliminary results suggest that PIEZO1 may regulate the browning process of white adipose tissue in an activity-dependent and activity-independent manner.

Our work identifies a central feedback mechanism by which mature adipocytes via Piezo1control adipogenesis during the development of obesity and suggests that Piezo1-mediated adipocyte mechanosignaling may be targeted to limit the metabolic complications of obesity (Wang S et al, Nat Comm 2020).

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.