Importance of the Microenvironment and Mechanosensing in Adipose Tissue Biology

Abstract

The expansion of adipose tissue is an adaptive mechanism that increases nutrient buffering capacity in response to an overall positive energy balance. Over the course of expansion, the adipose microenvironment undergoes continual remodeling to maintain its structural and functional integrity. However, in the long run, adipose tissue remodeling, typically characterized by adipocyte hypertrophy, immune cells infiltration, fibrosis and changes in vascular architecture, generates mechanical stress on adipose cells. This mechanical stimulus is then transduced into a biochemical signal that alters adipose function through mechanotransduction. In this review, we describe the physical changes occurring during adipose tissue remodeling, and how they regulate adipose cell physiology and promote obesity-associated dysfunction in adipose tissue.

Keywords: adipose tissue; mechanobiology; obesity.

Figure 1

Mechanosensing mechanisms in adipose tissue. Adipocytes receive mechanical forces at the cell plasma membrane arising from the surrounding extracellular matrix (ECM) or from neighboring cells via integrins, cadherins, GAP junctions or other mechanosensitive proteins such as SWELL1 or PIEZO channels. Mechanical cues can emanate from cell–cell adhesion, cell–ECM adhesion, cytoskeleton remodeling (actomyosin, stress fiber, etc.) and from the growth of lipid droplet (plasma membrane (PM)–lipid droplet (LD) forces) that stiffen the cells (purple arrows). Force sensing and transmission at cell–ECM and cell–cell adhesions converge on the cytoskeleton and can directly be transmitted to the nucleus, resulting in chromatin remodeling and transcriptional changes to modulate cell phenotype (inflammation, fibrosis, insulin resistance, and catecholamine resistance).

Figure 2

Microenvironment stiffness can regulate adipogenesis. During adipogenesis, the cells undergo substantial morphological modifications where spindle-shaped fibroblast-like preadipocytes become rounded mature adipocytes. There is an extensive reorganization of the cytoskeleton that allows lipid droplet growth and expansion. Upon adipogenic stimulation, the inhibition of Ras homolog family member A (RhoA) and Rho-associated protein kinases (ROCKs) disrupts actin cytoskeleton structures allowing adipogenesis. Thus, the inactive form, RHO GDP, promotes adipogenesis. However, in stiff environments, focal adhesion assembly is promoted, RHO GTP activates ROCK, which, in turn, activates F-actin stress fiber formation and translocation of YAP/TAZ to the nucleus, which breaks adipogenesis.

Figure 3

Hypothetical mechanical regulation of metabolism. Recent studies revealed that mechanical forces altered cell metabolism via cytoskeletal reorganization in cancer cells [194]. In a soft microenvironment, TRIM21 was not trapped by actin stress fiber bundles, which degrade phosphofructokinase (PFK). This led to low glycolysis rates. By contrast, when cells were surrounded by a stiff microenvironment (as in obese adipose tissue), TRIM21 was bound to the F-actin bundles of the cytoskeleton and thus PFK degradation was prevented, leading to high rates of glycolysis. By these mechanisms, we believe that mechanical cues could influence the metabolic phenotype and progression of adipose tissue dysfunction.

Figure 4

Roles of mechanosensitive channel in adipocyte. SWELL1/VRAC complex or Piezo1 channels are activated in response to increases in adipocyte volume. SWELL1/VRAC activation stimulates insulin–PI3K–AKT2 via GRB2, and thereby supports lipogenesis and continued adipocyte growth in a feed-forward manner [242] However, opening of Piezo1 in mature adipocytes causes the release of the adipogenic fibroblast growth factor 1 (FGF1), which induces adipogenesis through activation of the FGF-receptor-1 [243].