Overexpression of 1-acyl-glycerol-3-phosphate acyltransferase-alpha enhances lipid storage in cellular models of adipose tissue and skeletal muscle

Plasma nonesterified fatty acids (NEFA) at elevated concentrations antagoni ze insulin action and thus may play a critical role in the development of i nsulin resistance in type 2 diabetes. Plasma NEFA and glucose concentration s are regulated, in part, by their uptake into peripheral tissues. Cellular energy uptake can be increased by enhancing either energy transport or met abolism. The effects of overexpression of 1-acylglycerol-3-phosphate acyltr ansferase (AGAT)-alpha, which catalyzes the second step in triglyceride for mation from glycerol-3-phosphate, was studied in 3T3-L1 adipocytes and C2C1 2 myotubes. In myotubes, overexpression of AGAT-alpha did not affect total [C-14]glucose uptake in the presence or absence of insulin, whereas insulin -stimulated [C-14]glucose conversion to cellular lipids increased significa ntly (33%, P = 0.004) with a concomitant decrease (-30%, P = 0.005) in glyc ogen formation. [H-3]oleic acid (OA) uptake in AGAT-overexpressing myotubes increased 34% (P = 0.027) upon insulin stimulation. AGAT-alpha overexpress ion in adipocytes increased basal (130% P = 0.04) and insulin-stimulated (2 7%, P = 0.01) [H-3]OA uptake, increased insulin-stimulated glucose uptake ( 56%, P = 0.04) and conversion to cellular lipids (85%, P = 0.007), and supp ressed basal (-44%, P = 0.01) and isoproterenol-stimulated OA release (-45% , P = 0.03) but not glycerol release. Our data indicate that an increase in metabolic flow to triglyceride synthesis can inhibit NEFA release, increas e NEFA uptake, and promote insulin-mediated glucose utilization in 3T3-L1 a dipocytes. In myotubes, however, AGAT-alpha overexpression does not increas e basal cellular energy uptake, but can enhance NEFA uptake and divert gluc ose from glycogen synthesis to lipogenesis upon insulin stimulation.