Abstract
Chronic elevation of systemic levels of acute phase reactants and inflammatory cytokines found in patients with diabetes and the often-associated metabolic syndrome X (hypertriglyceridemia, low serum high density lipoprotein cholesterol, hypertension, and accelerated atherosclerosis) may be responsible for the increased incidence of cardiovascular problems in this population. Here we examine the contribution of adipose tissue to the systemic elevation of acute phase reactants associated with chronic hyperglycemia. We demonstrate that adipose tissue expresses a number of acute phase reactants at high levels, including serum amyloid A3 (SAA3), alphal-acid glycoprotein, the lipocalin 24p3 as well as plasminogen activator inhibitor-1 (PAI-1). Additionally, we show SAA3 is expressed at low levels under normal conditions but in the diabetic state is dramatically up-regulated in adipose tissue while down-regulated in liver. Furthermore, pro-inflammatory stimuli and high glucose can lead to the induction of SAA3 in adipose tissue in vivo as well as in the 3T3-L1 adipocyte cell line. Adipose tissue may therefore play a major role in the pathogenic sequelae of Type II diabetes, in particular the cardiovascular problems associated with prolonged hyperglycemia.
Highlights
Actively secrete and respond to inflammatory cytokines such as TNF␣, IL-1, and IL-6 (6 – 8)
We demonstrate that adipose tissue expresses a number of acute phase reactants at high levels, including serum amyloid A3 (SAA3), ␣l-acid glycoprotein, the lipocalin 24p3 as well as plasminogen activator inhibitor-1 (PAI-1)
Elevated Glucose Levels Lead to Induction of SAA3 in 3T3-L1 Adipocytes—Prompted by the observation that both hyperinsulinemic and insulinopenic model systems display an elevated level of SAA3 in adipose tissue, we addressed the question as to whether hyperglycemia alone could trigger SAA3 expression in vitro
Summary
Materials—Dulbecco’s modified Eagle’s medium was purchased from Cellgro Inc. Murine TNF␣ and IL-6 was purchased from Pharmingen. All rats received a primed-continuous (15– 40 Ci/min) infusion of high performance liquid chromatograph-purified [3-3H]glucose (PerkinElmer Life Sciences) throughout the study to determine glucose uptake. Hyperinsulinemic Euglycemic Clamp Studies—Lean rats received a primed continuous insulin infusion (3 milliunits/kg/min) and a variable infusion of 25% glucose periodically adjusted to maintain the plasma glucose concentration at the basal level of 7 mM for the duration of the study (3 h). This method enabled us to match the rate of glucose uptake observed in the above hyperglycemic clamp studies while maintaining euglycemia. Horseradish peroxidase-conjugated secondary antibodies were detected with enhanced chemiluminescence according to the manufacturer’s instructions (PerkinElmer Life Sciences)
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