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

Abstract

Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders.

Keywords: ANGPTL3; ANGPTL4; ANGPTL8; adipose tissue; adiposopathy; brown adipose tissue.

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 energy utilization [7,81,89].

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 with enhanced circulating glucocorticoids, typical of overnutrition. ANGPTL4 partly blocks WAT LPL, partly induces lipolysis and ceramide production [89]. Ceramide production is associated with worsening insulin resistance (IR) and inflammation, leading to WAT secretion of proinflammatory mediators, M1 macrophage infiltration, and adipocyte death typical of AT dysfunction [35,98].