FIGURE 1.

Regulation of adipocyte expansion. ① Lipid droplet growth is mediated via the balance between lipogenesis and lipolysis (black arrows, and see Supplementary Box S1). Insulin plays a role in promoting lipogenesis while inhibiting lipolysis, keeping lipid stored in adipocytes. ② EHD2 stabilizes caveolae on the cell membrane and disassembly of EHD2 facilitates caveolae to detach from the cell membrane, transporting the lipid-enriched membrane into the cytosol where it integrates into the lipid droplet (green arrows). ③ In response to mechanical stretch or osmotic pressure (red arrows), caveolae flatten, increasing cell membrane area. ④ Lipid droplet expansion and caveolae flattening activate SWELL/VARC ion channel complexes causing calcium ion efflux. TRPV4 ion channels sense changes in intracellular volume induced by lipid droplet enlargement, activating calcium ion influx. The activation of ion channels adjusts osmotic pressure and facilitates the cell to swell. In addition, the flattening of caveolae triggers a restructuring of the SWELL1/VRAC complex, destabilizing GRB2-IRS1 interactions and activating insulin-mediated growth signaling. ⑤ Insulin regulates lipogenesis and lipolysis (blue arrows), whilst also mediating activation of growth and mitogenic pathways, in order to accommodate the increased protein and transcript demands required for cell growth. Abbreviations: ACC, acetyl-CoA carboxylase; AKT, protein kinase B; AQP7, aquaglyceroporin-7; ATGL/HSL, adipose triglyceride lipase/hormone-sensitive lipase; EHD2, EH-domain–containing protein 2; FFA, free fatty acid; glucose-6-p, glucose-6-phosphatase; GLUT4, glucose transporter type 4; GRB2, growth factor receptor bound 2; IRS1, insulin receptor substrate 1; LPL, lipoprotein lipase; MGL, monoacylglycerol lipase; PCK1, phosphoenolpyruvate carboxykinase; PI3K, phosphatidylinositol-3-kinase; TG, triglyceride; TRPV4, transient receptor potential vanilloid 4.