A reduced pancreatic protein secretion in response to cholecystokinin (CCK) in the obese Zucker rat correlates with a reduced receptor capacity for CCK.
Pancreatic membrane receptors for cholecystokinin (CCK) in obese and nonobese Zucker rats were compared with the use of a biologically active [125I]iodo-CCK-8 radioprobe. Membrane homogenates from obese rats bound half the amount of radioligand in 2 h as did membranes from lean rats (specifically bound, 7.0% vs. 14.0%; P less than 0.001). The reduced binding in membranes from obese rats did not result from kinetic effects or radioligand degradation; similar rates of association and dissociation of [125I]iodo-CCK-8 were obtained in membrane preparations from both, and no differences were found in the extent of radioligand degradation in the two membrane preparations. These differences also did not reflect an effect of cell size, as pancreatic acinar cells from obese and nonobese rats had about the same perimeters (24.6 and 26.3 micron, respectively) and areas (30.1 and 34.2 micron 2, respectively). Scatchard-type plots of competitive displacement data for CCK-binding sites on pancreatic membranes from both genotypes were curvilinear and were analyzed by a two-site binding model. The Kd values for both the high (0.56 vs. 0.45 nM) and low (9.0 vs. 14 nM) affinity sites on membranes from nonobese and obese rats, respectively, were the same (P greater than 0.1), whereas the capacities for CCK in the high (365 vs. 165 fmol/mg protein) and low (1020 vs. 360 fmol/mg protein) affinity regions were significantly different (P less than 0.025). This difference in CCK receptor capacity was reflected by a reduced pancreatic protein secretory response in the obese rat. After injections of 40, 80, 160, and 320 ng CCK/kg BW, total pancreatic protein secretion in nonobese rats increased 5, 12, 19, and 21 times above basal levels, whereas the same doses caused 2-, 6-, 12-, and 13-fold increases in obese rats. Whereas the reduced secretion in the obese rat may reflect a difference in the intracellular machinery leading to protein secretion between the two genotypes, these data are more consistent with a direct mechanism, whereby reduced numbers of pancreatic receptors for CCK are responsible for reduced protein secretion.
D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D009765:Obesity / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011949:Receptors, Cholecystokinin; D012844:Sincalide / Q000378:metabolism / Q000494:pharmacology*
D007457:Iodine Radioisotopes; D011506:Proteins; D011956:Receptors, Cell Surface; D011949:Receptors, Cholecystokinin; D012844:Sincalide