The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

Figures

• 

  Figure 1. The angiopoietin-like system (ANGPTLs) model in healthy adipose tissue. Legend: functioning of ANGPTL system in healthy adipose tissue. Dotted lines report data with a low level of evidence. Panels (A,B) describe the hepatocyte function in feeding and fasting. In response to insulin increase (A), hepatocytes secrete ANGPTL8, and ANGPTL3. ANGPTL3-8 tetramers inhibit lipoprotein lipase (LPL) in oxidative tissues [7,68]. Reduced blood glucose in fasting (B) leads to increased circulating glucocorticoids and glucagon that induce ANGPTL4 expression [82,94]. In the liver, ANGPTL4 expression possibly enhances lipogenesis and gluconeogenesis, VLDL production, and secretion, as proved in mouse models [89]. Panels (C,D) describe white adipocyte function in feeding and fasting. During feeding (C), insulin enhances nuclear expression of ANGPTL8 determining a block in lipolysis and enhanced insulin sensibilization, adiponectin secretion, and M2 polarization of resident macrophages [67,68,71]. In fasting (D) ANGPTL4 is expressed both in nucleoplasm and secreted [74,75,84,86,94]. In this physiologic condition, lipolysis is functional to liberate free fatty acids (FFA) deposit and promotes…

• 

  Figure 2. ANGPTLs model of adipose tissue dysfunction. Legend: possible induction mechanism of adipose tissue dysfunction involving ANGPTL3-4-8. Dotted lines report data with a low level of evidence. Panel (A) describes dysregulation of hepatocytes function in conditions of chronic overnutrition: overexpressed insulin levels together with elevated plasma glucocorticoids in obese patients induce both ANGPTL8 and ANGPTL4 expression in hepatocytes [68,73,74,75,84,86,89,94]. ANGPTL4 possibly induces ceramides production; therefore, worsening hepatic insulin resistance and liver steatosis [35,81,89]. Panel (B) describes white adipose tissue (WAT) dysfunction in conditions of chronic overnutrition, potentially mediated by ANGPTLs system disruption: excess insulin induces overexpression of nuclear ANGPTL8 in WAT [67,68]. ANGPTL8 in turn enhances insulin signaling via AKT phosphorylation, chronic AKT phosphorylation induces worsening insulin resistance [73]. Permanent block in lipolysis leads to adipocyte mass expansion over oxygen diffusion capacity, this creates adipocyte stress and hypoxia-inducible factor 1-alpha (HIF1α) induction, which in turn induces ANGPTL4 expression [83,84], together…