Variable Changes of Circulating ANGPTL3 and ANGPTL4 in Different Obese Phenotypes: Relationship with Vasodilator Dysfunction

Abstract

Obesity associates with premature atherosclerosis and an increased burden of cardiovascular disease, especially when accompanied by abnormalities of lipid and glucose metabolism. Angiopoietin-like (ANGPTL)3 and ANGPTL4 are metabolic regulators, whose upregulation is associated with dyslipidemia, insulin resistance and atherosclerosis. We analyzed, therefore, changes in circulating ANGPTL3 and ANGPTL4 in obese patients with different metabolic phenotypes and their relation with impaired vasodilator reactivity, an early abnormality in atherosclerosis. Compared to the lean subjects (n = 42), circulating ANGPTL3 was elevated (both p > 0.001) in the patients with metabolically unhealthy obesity (MUO; n = 87) and type 2 diabetes (T2D; n = 31), but not in those with metabolically healthy obesity (MHO; n = 48, p > 0.05). Circulating ANGPTL4, by contrast, was increased in all obese subgroups (all p < 0.001 vs. lean subjects). Vasodilator responses to both acetylcholine and sodium nitroprusside were reduced in the three obese subgroups vs. lean subjects (all p < 0.001), with greater impairment in the patients with T2D than in those with MHO and MUO (all p < 0.05). In the whole population, an inverse relationship (r = 0.27; p = 0.003) was observed between circulating ANGPTL4 and endothelium-dependent vasorelaxation. Circulating ANGPTL3 and ANGPTL4 undergo variable changes in obese patients with different metabolic phenotypes; changes in ANGPTL4 relate to endothelial dysfunction, making this protein a possible target for vascular prevention in these patients.

Association of Metabolically Healthy and Unhealthy Obesity Phenotype with Markers Related to Obesity, Diabetes among Young, Healthy Adult Men. Analysis of MAGNETIC Study

“…However, contrary to our results, this was not the case for MHO. ANGPTL4 was significantly elevated in all obese subgroups in their work in contrast to our results [60]. In line with the findings of Schinzari et al, our results suggest a different mechanism related to the dysregulation of ANGPTL3 and ANGPTL4 in patients with excessive fat mass.…”

“…It is worth mentioning here that previous works measuring ANGPTL3 levels in insulin resistance states such as obesity and T2D have produced conflicting results. Most studies report increased circulation of ANGPTL3 in obese or T2D patients [60,61], while other studies have found that ANGPTL3 levels are not higher in obese subjects than in controls [62].…”

Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk

“…Based on our data, it is probable that the effects of these hepatokines on adipocytes synergize, together with other pathological mechanisms, to promote fat mass expansion and obesity. Circulating levels of AHSG [ 68 , 69 ], ANGPTL4 [ 70 , 71 ] and LECT2 [ 14 , 72 , 73 ] were previously demonstrated to correlate with obesity, BMI or waist circumference in humans. Although these hepatokines are predominantly expressed by the liver, mouse and human adipocytes were also reported to produce them [ 74 , 75 , 76 , 77 ], therefore suggesting both endocrine and paracrine action of these factors on AT homeostasis.…”

The Role of Endothelial Progenitor Cells in Atherosclerosis and Impact of Anti-Lipemic Treatments on Endothelial Repair

“…The mechanism of action involves a complex of Angptl3 with the related protein Angptl8, that promotes Angptl3 effects [ 120 , 122 , 123 ]. Beyond lipid-lowering, inhibition of Angptl3 was shown to improve endothelial function [ 124 ]. This effect may be mediated indirectly through improved lipid levels, but also directly by binding endothelial integrin v3, and by stimulating Wnt/-catenin signaling [ 12 ].…”