Autotaxin Is Regulated by Glucose and Insulin in Adipocytes.
Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study examined the regulation of ATX in adipocytes by glucose and insulin and the role of ATX in adipocyte metabolism. Induction of insulin resistance in adipocytes with high glucose and insulin concentrations increased ATX secretion, whereas coincubation with the insulin sensitizer, rosiglitazone, prevented this response. Moreover, glucose independently increased ATX messenger RNA (mRNA), protein, and activity in a time- and concentration-dependent manner. Glucose also acutely upregulated secreted ATX activity in subcutaneous adipose tissue explants. Insulin elicited a biphasic response. Acute insulin stimulation increased ATX activity in a PI3Kinase-dependent and mTORC1-independent manner, whereas chronic insulin stimulation decreased ATX mRNA, protein, and activity. To examine the metabolic role of ATX in 3T3-L1 adipocytes, we incubated cells with the ATX inhibitor, PF-8380, for 24 hours. Whereas ATX inhibition increased the expression of peroxisome proliferator-activated receptor-γ and its downstream targets, insulin signaling and mitochondrial respiration were unaffected. However, ATX inhibition enhanced mitochondrial H2O2 production. Taken together, this study suggests that ATX secretion from adipocytes is differentially regulated by glucose and insulin. This study also suggests that inhibition of autocrine/paracrine ATX-lysophosphatidic acid signaling does not influence insulin signaling or mitochondrial respiration, but increases reactive oxygen species production in adipocytes.
Dalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, Canada.
Kenneth
K
D'Souza
Department of Human Kinetics, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, Canada.
Daniel A
DA
Kane
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada.
Mohamed
M
Touaibia
Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
Erin E
EE
Kershaw
Dalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, Canada.
Thomas
T
Pulinilkunnil
Dalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, Canada.
Petra C
PC
Kienesberger
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D000099189:Lysophospholipase D
D005947:Glucose; D007328:Insulin; D010727:Phosphoric Diester Hydrolases; D012333:RNA, Messenger; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D000099189:Lysophospholipase D