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The Endogenous Cannabinoid System Stimulates Glucose Uptake in Human Fat Cells via Phosphatidylinositol 3-Kinase and Calcium-Dependent Mechanisms

Endocrine-Metabolic Laboratory (C.Pa., C.Pi., A.C., R.U., M.R., G.M., G.F., R.V.) and Institute of Surgical Pathology (P.B.), Department of Medical and Surgical Sciences, University of Padova, 35128 Padova, Italy; and Section of General Pathology (K.B., R.R.), Department of Experimental and Diagnostic Medicine, University of Ferrara, 44100 Ferrara, Italy

Address all correspondence and requests for reprints to: Dr. Claudio Pagano, M.D., Ph.D., Endocrine-Metabolic Laboratory, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale 105, 35100 Padova, Italy. E-mail: claudio.pagano{at}unipd.it.

Background: The endogenous cannabinoid system participates in the regulation of energy balance, and its dysregulation may be implicated in the pathogenesis of obesity. Adipose tissue endocannabinoids may produce metabolic and endocrine effects, but very few data are available in human adipose tissue and in primary human fat cells.

Experimental Design: We measured expression of type 1 and type 2 cannabinoid receptors (CNR), enzymes of cannabinoids synthesis and degradation in human omental, sc abdominal, and gluteal adipose tissue from lean and obese subjects. Furthermore, we assessed the effect of CNR1 stimulation on glucose uptake and intracellular transduction mechanisms in primary human adipocytes. Then we assessed the reciprocal regulation between CNR1 and peroxisome proliferator-activated receptor- (PPAR). Finally, we tested whether leptin and adiponectin are regulated by CNR1 in human adipocytes.

Results: We found that most genes of the endocannabinoid system are down-regulated in gluteal fat and up-regulated in visceral and sc abdominal adipose tissue of obese patients. Treatment of adipocytes with rosiglitazone markedly down-regulated CNR1 expression, whereas Win 55,212 up-regulated PPAR. Win 55,212 increased (+50%) glucose uptake, the translocation of glucose transporter 4, and intracellular calcium in fat cells. All these effects were inhibited by SR141716 and wortmannin and by removing extracellular calcium. Win 55,212 and SR141716 had no effect on expression of adiponectin and leptin.

Conclusions: These results indicate a role for the local endocannabinoids in the regulation of glucose metabolism in human adipocytes and suggest a role in channeling excess energy fuels to adipose tissue in obese humans.

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