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.
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.