bw-a1433 and Obesity

Earlier studies have shown that whole body adenosine receptor antagonism increases skeletal muscle insulin sensitivity in insulin-resistant Zucker rats. To find which steps in the insulin signaling pathway are influenced by adenosine receptors, muscle from lean and obese Zucker rats, treated for 1 week with the adenosine receptor antagonist, 1,3-dipropyl-8-(4-acrylate)-phenylxanthine (BWA1433), were analyzed. All rats were first anesthetized and injected intravenously (i.v.) with 1 IU of insulin. About 3 min later the gastrocnemius was freeze clamped. Insulin receptors were partially purified on wheat germ agglutinin (WGA) columns and insulin receptor kinase activity measured in control and BWA1433-treated lean and obese Zucker rats. Protein tyrosine phosphatase (PTPase) activity was also analyzed in subcellular fractions, including the cytosolic fraction, a high-speed particulate fraction and the insulin receptor fraction eluted from WGA columns. Administration of BWA1433 increased insulin receptor kinase activity in obese but not lean Zucker rats. PTPase activities were higher in the untreated obese rat muscle particulate fractions than in the lean rat particulate fractions. The BWA1433 administration lowered the PTPase activity of the obese rats but not the lean rats. Although the PTPase activity in WGA eluate fractions containing crude insulin receptors were similar in lean and obese animals, BWA1433 administration was found to lower the PTPase activities in the fractions obtained from obese but not from the lean rats. PTPases may be upregulated in muscles from obese rats due to activated adenosine receptors. Adenosine receptor blockade, by reducing PTPase activity, may thereby increase insulin signaling.

Topics: Animals; Electrophoresis; Female; Insulin; Male; Muscle, Skeletal; Obesity; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Purinergic P1 Receptor Antagonists; Rats; Rats, Zucker; Receptors, Purinergic P1; Signal Transduction; Xanthines

The A1 adenosine receptor (A1ar) antagonist 1,3-dipropyl-8-(p-acrylic)-phenylxanthine (BW-1433) was administered to lean and obese Zucker rats to probe the influence of endogenously activated A1ars on whole body energy metabolism. The drug induced a transient increase in lipolysis as indicated by a rise in serum glycerol in obese rats. The disappearance of the response by day 7 of chronic studies was accompanied by an increase in A1ar numbers. Glucose tolerance tests were administered to rats treated with BW-1433. Peak serum insulin levels and areas under glucose curves (AUGs) were 34 and 41% lower in treated obese animals than in controls, respectively, and 19 and 39% lower in lean animals. With chronic administration (6 wk), AUGs decreased 47 and 33% in obese and lean animals, respectively. There was no effect of BW-1433 in either lean or obese rats on weight gain or percent body fat. Thus the major sustained influence of whole body A1ar antagonism in both lean and obese animals was an increase in whole body glucose tolerance at lower levels of insulin.

Topics: Adipocytes; Adipose Tissue; Administration, Oral; Animals; Brain; Female; Glucose; Glucose Tolerance Test; Glycerol; Insulin Resistance; Lipolysis; Male; Muscle, Skeletal; Obesity; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Rats, Zucker; Xanthines

Previous studies have shown that treatment of obese Zucker rats with the adenosine receptor antagonist 1,3-dipropyl-8-(p-acrylic) phenyl xanthine (BWA1433) improves intraperitoneal glucose tolerance. In this study, a euglycemic hyperinsulinemic clamp was performed on obese (fa/fa) and lean (Fa/fa) Zucker rats that had been treated orally with BWA1433 or vehicle for 1 wk. A constant infusion of [3H]glucose was initiated in fasted animals to measure basal whole body glucose kinetics. No differences in glucose concentration or rates of glucose production/disappearance were observed between lean or obese animals with or without BWA1433. During the euglycemic hyperinsulinemic clamp, whole body glucose disposal in obese Zucker rats was only 22% of that observed in lean animals. BWA1433 treatment increased glucose disposal by 88% in obese Zucker rats. At the end of the clamp, [14C]-2-deoxyglucose was injected to determine tissue-specific differences in glucose uptake. Gastrocnemius, soleus, heart, and liver of untreated obese animals had significantly lower glucose uptake than lean controls under hyperinsulinemic conditions. BWA1433 treatment of obese animals increased glucose uptake in gastrocnemius and soleus muscles by 44 and 47%, respectively. Conversely, BWA1433 treatment decreased glucose uptake in adipose tissue by 54 and 49% in obese and lean Zucker rats, respectively. In summary, BWA1433 improves glucose tolerance by increasing glucose uptake in skeletal muscle while decreasing glucose uptake by adipose tissue. This study suggests that insulin resistance in obese Zucker rats is tissue specific and that signaling from adenosine receptors may be a factor contributing to tissue-specific insulin resistance.

Topics: Adipose Tissue; Animals; Biological Transport, Active; Deoxyglucose; Glucose; Hyperinsulinism; Insulin Resistance; Liver; Muscle, Skeletal; Myocardium; Obesity; Organ Specificity; Purinergic P1 Receptor Antagonists; Rats; Rats, Zucker; Xanthines