title: Improved adipose tissue metabolism after 5-year growth hormone replacement therapy in growth hormone deficient adults: The role of zinc-α2-glycoprotein.
abstract: Growth hormone (GH) supplementation therapy to adults with GH deficiency has beneficial effects on adipose tissue lipid metabolism, improving thus adipocyte functional morphology and insulin sensitivity. However, molecular nature of these effects remains unclear. We therefore tested the hypothesis that lipid-mobilizing adipokine zinc-α2-glycoprotein is causally linked to GH effects on adipose tissue lipid metabolism. Seventeen patients with severe GH deficiency examined before and after the 5-year GH replacement therapy were compared with age-, gender- and BMI-matched healthy controls. Euglycemic hyperinsulinemic clamp was used to assess whole-body and adipose tissue-specific insulin sensitivity. Glucose tolerance was determined by oGTT, visceral and subcutaneous abdominal adiposity by MRI, adipocyte size morphometrically after collagenase digestion, lipid accumulation and release was studied in differentiated human primary adipocytes in association with GH treatment and zinc-α2-glycoprotein gene silencing. Five-year GH replacement therapy improved glucose tolerance, adipose tissue insulin sensitivity and reduced adipocyte size without affecting adiposity and whole-body insulin sensitivity. Adipose tissue zinc-α2-glycoprotein expression was positively associated with whole-body and adipose tissue insulin sensitivity and negatively with adipocyte size. GH treatment to adipocytes in vitro increased zinc-α2-glycoprotein expression (>50%) and was paralleled by enhanced lipolysis and decreased triglyceride accumulation (>35%). Moreover, GH treatment improved antilipolytic action of insulin in cultured adipocytes. Most importantly, silencing zinc-α2-glycoprotein eliminated all of the GH effects on adipocyte lipid metabolism. Effects of 5-year GH supplementation therapy on adipose tissue lipid metabolism and insulin sensitivity are associated with zinc-α2-glycoprotein. Presence of this adipokine is required for the GH action on adipocyte lipid metabolism in vitro.
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Balaž
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia ; Institute of Pathophysiology; Faculty of Medicine; Comenius University ; Bratislava, Slovakia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ukropcova
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Timea
authors.initials: T
authors.lastname: Kurdiova
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Vlcek
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Martina
authors.initials: M
authors.lastname: Surova
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Patrik
authors.initials: P
authors.lastname: Krumpolec
authors.affiliation: National Institute of Endocrinology and Diabetology ; Lubochna, Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Vanuga
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gašperíková
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Iwar
authors.initials: I
authors.lastname: Klimeš
authors.affiliation: 5th Department of Internal Medicine; University Hospital; Faculty of Medicine; Comenius University ; Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Payer
authors.affiliation: Institute of Food; Nutrition and Health; Swiss Federal Institute of Technology; ETH Zurich ; Schwerzenbach, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolfrum
authors.affiliation: Institute of Experimental Endocrinology; Slovak Academy of Sciences ; Bratislava, Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Ukropec
keywords: ACC1, acetyl-CoA carboxylase 1; BSA, bovine serum albumin; DGAT, diacylglycerol acyltransferase; DMEM, Dulbecco's Modified Eagle Medium; EHC, euglycemic hyperinsulinemic clamp; FABP4, fatty acid binding protein 4; FAS, fatty acid synthase; FBS, fetal bovine serum; FFA, free fatty acids; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GH, growth hormone; GHD, growth hormone deficiency; GLUT4, glucose transporter 4; HSL, hormone sensitive lipase; IGF-1, insulin-like growth factor 1; IRS1, insulin receptor substrate 1; MRI, magnetic resonance imaging; PPARGC1A, peroxisome proliferator-activated receptor 1 gamma coactivator 1 α; RPL13A, ribosomal protein L13a; TG, triglycerides; ZAG, zinc-α2-glycoprotein.; adipocyte size; adipose tissue; glucose tolerance; growth hormone deficiency; growth hormone replacement therapy; insulin sensitivity; lipolysis; oGTT, oral glucose tolerance test; rhGH, recombinant human growth hormone