Angiopoietin-Like Protein 4 Overexpression in Visceral Adipose Tissue from Obese Subjects with Impaired Glucose Metabolism and Relationship with Lipoprotein Lipase.

Ilaria Barchetta,Laura Bertoccini,Frida Leonetti,Flavia Agata Cimini,Claudio Di Cristofano,Amalia Gastaldelli,Melania Gaggini,Marco Giorgio Baroni,Caterina Chiappetta,Maria Gisella Cavallo,Andrea Lenzi,Gianfranco Silecchia,Valentina Ceccarelli

doi:10.3390/ijms21197197

Abstract

Angiopoietin-like protein 4 (ANGPTL4) regulates lipid partitioning by inhibiting circulating and tissue lipoprotein lipase (LPL); ANGPTL4 loss-of-function variants improve insulin sensitivity and reduce type 2 diabetes (T2D) risk with mechanisms partially unknown. This study was designed to explore metabolic implications of differential ANGPTL4 and LPL expression in human adipose tissue (AT). We recruited eighty-eight obese individuals, with and without abnormal glucose metabolism (AGM), undergoing bariatric surgery; visceral AT (VAT) fragments were obtained intra-operatively and analyzed by immunohistochemistry and mRNA by rt-PCR. Data on hepatic ANGPTL4 mRNA were available for 40 participants. VAT ANGPTL4 expression was higher in AGM individuals than in those with normal glucose tolerance (NGT) and associated with VAT inflammation, insulin resistance, and presence of adipocyte size heterogeneity. Increased ANGPTL4 was associated with AGM with OR = 5.1 (95% C.I.: 1.2–23; p = 0.02) and AUROC = 0.76 (95% C.I.: 1.2–23; p < 0.001). High LPL was associated with the detection of homogeneous adipocyte size, reduced microvessel density, and higher HIF-1α levels and inversely correlated to blood transaminases. In conclusion, in obese individuals, VAT ANGPTL4 levels are increased in the presence of local inflammation and AGM. Conversely, higher LPL expression describes a condition of increased lipid storage in adipocytes, which may serve as a protective mechanism against ectopic fat accumulation and related metabolic disease in obesity.

Highlights

The angiopoietin-like proteins (ANGPTLs) are secreted factors structurally similar to angiopoietins; among them, ANGPTL3, 4, and 8 play a fundamental role in the regulation of lipid metabolism, mainly by binding to circulating lipoprotein lipase (LPL) and antagonizing its activity [1,2]
The overall effect of the selective LPL inhibition by ANGPTLs is the margination of triglyceride-rich lipoproteins (TRLs) in the capillary lumen, and the unloading of free fatty acids (FFAs) in vital organs, such as heart, skeletal muscle, and adipose tissue (AT), where FFAs serve as a fuel for energetic metabolism
50% fulfilled the criteria for metabolic syndrome (MS) diagnosis and 26% (23 out of 88 subjects) had abnormal glucose metabolism (AGM), as considered as impaired glucose regulation (n= 14/23, among whom n = 11 with impaired fasting glucose (IFG) and n = 3 with IFG + impaired glucose tolerance (IGT)) or type 2 diabetes (T2D) (n= 9/23)

Summary

Introduction

The angiopoietin-like proteins (ANGPTLs) are secreted factors structurally similar to angiopoietins; among them, ANGPTL3, 4, and 8 play a fundamental role in the regulation of lipid metabolism, mainly by binding to circulating lipoprotein lipase (LPL) and antagonizing its activity [1,2]. Short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induces activation of LPL [7]; clinical trials have shown initial favorable effects with ANGPTL3 and ANGPTL4 antagonists on lipid profile and cardiovascular risk reduction [8]. ANGPTL4 was shown to be involved in glucose metabolism, findings in this regard are not conclusive, as ANGPTL4 overexpression in mice has been associated to either improved or impaired glucose tolerance in different studies [9,10,11]. Experimental ANGPTL4 knockout in mice improved insulin sensitivity and glucose homeostasis and, a role of ANGPTL4 antagonist in T2D therapy has been hypothesized [7]

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