Association of serum angiopoietin-like protein 2 and epinephrine levels in metabolically healthy but obese individuals: In vitro and in vivo evidence

In the present study, we explored the association of serum angiopoietin-like protein 2 (ANGPTL2) levels with insulin sensitivity and serum epinephrine levels in metabolically healthy but obese (MHO) subjects. We also investigated the effects of epinephrine on ANGPTL2 expression in adipocytes in vitro. We examined the metabolic characteristics and serum ANGPTL2 and epinephrine levels in 100 non-diabetic obese postmenopausal women. Subjects were classified as MHO (n=25) or at-risk (n=25) based on the upper and lower quartiles of insulin sensitivity, respectively. Differentiated 3T3-L1 adipocytes were treated with increasing doses of epinephrine (10, 30 and 50 nM) in the presence or absence of phentolamine (10 mu M), propranolol (0.3 mu M), LY294002 (50 mu M) or protein kinase A inhibitor fragment 6-22 amide (PKAI, 1 mM) for 24 h. We observed that serum ANGPTL2 levels were negatively correlated with insulin sensitivity (r=-0.23, P=0.021) and serum epinephrine level (r=-0.62, P<0.001) in the study subjects, with the MHO subjects displaying significantly lower serum ANGPTL2 and higher serum epinephrine levels than the at-risk subjects. Epinephrine reduced the ANGPTL2 mRNA and protein levels in differentiated 3T3-L1 adipocytes in a dose-dependent manner. Propranolol and PKAI were able to eliminate this reduction in ANGPTL2 levels whereas phentolamine and LY294002 were not. The in vitro findings indicated that epinephrine decreased ANGPTL expression at the mRNA and protein levels via the beta-adrenoceptors and the PKA signaling pathway. This study suggests that beta-receptor activation helps to maintain the metabolic profile of MHO individuals and prevent type 2 diabetes mellitus (T2DM) by decreasing serum ANGPTL2 levels.