Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression
Autotaxin is a lysophospholipase D that is secreted by adipocytes and whose expression is substantially up-regulated in obese, diabetic db/db mice. The aim of the present study was to depict the physiopathological and cellular mechanisms involved in regulation of adipocyte autotaxin expression.
Autotaxin mRNAs were quantified in adipose tissue from db/db mice (obese and highly diabetic type 2), gold-thioglucose-treated (GTG) mice (highly obese and moderately diabetic type 2), high-fat diet-fed (HFD) mice (obese and moderately diabetic type 2), streptozotocin-treated mice (thin and diabetic type 1), and massively obese humans with glucose intolerance.
When compared to non-obese controls, autotaxin expression in db/db mice was significantly increased, but not in GTG, HFD, or streptozotocin-treated mice. During db/db mice development, up-regulation of autotaxin occurred only 3 weeks after the emergence of hyperinsulinaemia, and simultaneously with the emergence of hyperglycaaemia. Adipocytes from db/db mice exhibited a stronger impairment of insulin-stimulated glucose uptake than non-obese and HFD-induced obese mice. Autotaxin expression was up-regulated by treatment with TNFα (insulin resistance-promoting cytokine), and down-regulated by rosiglitazone treatment (insulin-sensitising compound) in 3T3F442A adipocytes. Finally, adipose tissue autotaxin expression was significantly up-regulated in patients exhibiting both insulin resistance and impaired glucose tolerance.
The present work demonstrates the existence of a db/db-specific up-regulation of adipocyte autotaxin expression, which could be related to the severe type 2 diabetes phenotype and adipocyte insulin resistance, rather than excess adiposity in itself. It also showed that type 2 diabetes in humans is also associated with up-regulation of adipocyte autotaxin expression.
- Jazet IM, Pijl H, Meinders AE (2003) Adipose tissue as an endocrine organ: impact on insulin resistance. Neth J Med 61:194–212
- Ferry G, Tellier E, Try A et al (2003) Autotaxin is released from adipocytes, catalyses lysophosphatidic acid synthesis, and activates preadipocyte proliferation: up-regulated expression with adipocyte differentiation and obesity. J Biol Chem 278:18162–18169 CrossRef
- Goding JW, Grobben B, Slegers H (2003) Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Biochim Biophys Acta 1638:1–19
- Umezu-Goto M, Kishi Y, Taira A et al (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158:227–233 CrossRef
- Tokumura A, Majima E, Kariya Y et al (2002) Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 277:39436–39442 CrossRef
- Luquain C, Sciorra VA, Morris AJ (2003) Lysophosphatidic acid signaling: how a small lipid does big things. Trends Biochem Sci 28:377–383 CrossRef
- Morin N, Lizcano JM, Fontana E et al (2001) Semicarbazide-sensitive amine oxidase substrates stimulate glucose transport and inhibit lipolysis in human adipocytes. J Pharmacol Exp Ther 297:563–572
- Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502
- Gesta S, Simon M, Rey A et al (2002) Secretion of a lysophospholipase D activity by adipocytes: involvement in lysophosphatidic acid synthesis. J Lipid Res 43:904–910
- Shafrir E (1992) Animal models of non-insulin-dependent diabetes. Diabetes Metab Rev 8:179–208
- Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 14:447–455 CrossRef
- American Diabetes Association (1997) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183–1197
- Tokumura A, Kanaya Y, Kitahara M, Miyake M, Yoshioka Y, Fukuzawa K (2002) Increased formation of lysophosphatidic acids by lysophospholipase D in serum of hypercholesterolemic rabbits. J Lipid Res 43:307–315
- Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression
Volume 48, Issue 3 , pp 569-577
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- Author Affiliations
- 1. INSERM U586, Institut Louis Bugnard, Rangueil Hospital, TSA 50032, 31059, Toulouse Cedex 9, France
- 2. Service for Diabetology, Metabolic Diseases and Nutrition, CHU de Nancy, Hopital J d’Arc, 54201, Toul cedex, France
- 3. Centre de Recherche de Croissy, Institut de Recherche Servier, 78290, Croissy-sur-Seine, France