Endocrine Abstracts

Context: Angiopoietin-like protein 4 (Angptl4) is a protein involved in lipolysis, that is regulated by non-esterified free fatty acids (FFA). GH promotes lipolysis and increases circulating FFA. Hypothesis: GH increases circulating Angptl4 levels by modulating its expression and secretion from fat and muscle. Angptl4 might be of metabolic relevance for the insulin resistance associated with GH/IGF1 excess or deficiency.

Objective: To evaluate Angptl4 in acromegaly (ACRO) and adult onset GHD (aoGHD) before and after treatment. Furthermore, to assess the in vitro effects of GH/IGF1 on Angptl4 gene expression and protein secretion in human visceral (VA) and subcutaneous (SC) adipocytes, hepatocytes, endothelial cells (HUVEC), and rat H9C2 muscle cells.

Design and patients: Body composition (DXA), glucose metabolism parameters, FFA and Angptl4 were measured in two study populations: a cohort of patients with ACRO at baseline (n=94) and after treatment (n=58), and a cohort of patients with aoGHD (n=39) before, and after receiving GH substitution (9 months, placebo/controlled).

Results: At baseline Angptl4 was positively associated with serum FFA (ACRO, r=0.48, P<0.001 and aoGHD, r=0.47, P=0.003). Angptl4 was correlated with body fat (r=0.46, P=0.027) in aoGHD, whereas no correlation with body fat or glucose metabolism parameters was found in ACRO. In ACRO Angptl4 decreased (62 (40) ng/ml vs 54 (30) ng/ml, P<0.001) and FFA did not change (0.509±0.22 mEq/l vs 0.516±0.23 mEq/l, P=0.633) with treatment. The decrease of Angptl4 was associated with the decrease of GH (r=0.55, P=0.005). In aoGHD Angptl4 (54 (28) ng/ml vs 74 (37) ng/ml, P<0.001) and FFA (0. 471±0.19 mEq/l vs 0.557±0.22 mEq/l, P=0.009) increased significantly during active treatment. The increase of Angptl4 was strongly associated with the increase of FFA (r=0.70, P<0.001). In vitro GH, but not IGF1, increased Angptl4 gene expression and protein secretion from mature SC and VA adipocytes, effect blocked after the addition of GH receptor antibody. No effect was recorded in human hepatocytes, HUVEC and rat muscle cells.

Conclusion: i) GH increases Angptl4 in patients, an effect most probably mediated by the circulating FFA. ii) Angptl4 does not directly regulate glucose homeostasis associated with GH/IGF1 excess or deficiency. iii) Adipocytes, respond to GH stimulation, and should be considered a source of Angptl4.