Biomedical subjects
Publications and source records attributed to J Christophe.
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1. The activation of rat pancreatic adenylate cyclase by guanosine 5'-(beta-gamma-imido)triphosphate (p[NH]ppG) and GTP, and by the two gastrointestinal hormones pancreozymin (as C-terminal octapeptide) and secretin was correlated with the binding of [8-3H]guanosine 5'-(beta-gamma-imido)triphosphate to rat pancreatic plasma membranes. 2. The low basal adenylate cyclase activity was stimulated 17-fold by p[NH]ppG (after a 2 min lag period), 3,5-fold only by GTP, 21-fold by C-terminal octapeptide of pancreozymin, and 8-fold by secretin. GTP inhibited competitively the activation of adenylate cyclase by p[NH]ppG with a Ki,app almost identical with the Ka,app (0.3 micron). p[NH]ppG and GTP enhanced the stimulation by secretin more markedly than that by the C-terminal octapeptide of pancreozymin, leading to the same maximal activity. Both hormones suppressed the lag period of activation by p[NH]ppG. 3. The binding of [8-3H]p[NH]ppG was dependent on time, temperature and Mg2+ and it was also a saturable and reversible process. Scatchard plots with a concavity upward were linearized after co-addition of ATP, Mg2+ and an ATP-regenerating system that abolished low-affinity sites for p[NH]ppG without saturating higher affinity sites, GTP, ITP and UTP inhibited [8-3H]p[NH]ppG binding to the high-affinity sites in concentration ranges identical with those found for adenylate cyclase activation. Considerable binding of [8-3H]p[NH]ppG was still evident at 20 degrees C, but enzyme activation was not observed any more, except in the presence of hormones.
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Plasma cyclic AMP levels were determined during a 40 minute secretin infusion (1 Cl.U kg-1h-1) followed by a 40 minute combined secretin (1 Cl.U kg-1h-1) caerulein (75 ng kg-1h-1) infusion. In nine healthy subjects, both secretin alone and secretin in combination with caerulein did not affect plasma cyclic AMP levels. The same was observed in six patients with chronic pancreatitis. By contrast, in patients suffering from liver disease (nine cases) or extrahepatic cholestasis (six cases), secretin elicited large increases in plasma cyclic AMP concentration; the mean values attained being, respectively, seven and four times higher than before the infusion. On the other hand, increases in plasma cyclic AMP 10 minutes after a bolus injection of glucagon (1 mg) were four times lower in the liver disease group as compared to the controls. The results reported here suggest that the liver plays a major role in the degradation of plasma cyclic AMP produced by target tissues responding to secretin, and in the release of cyclic AMP under glucagon. Liver disease reduce the capacity of the liver to clear cyclic AMP from the blood. The pancreas does not contribute significantly to the cyclic AMP in the blood.
Male rats were submitted for 3 wk either to portacaval shunt or to portacaval transposition. In both cases, sham-operated pair-fed rats served as controls. After an overnight fast, insulinemia was similar in all groups, but glucagonemia was significantly higher (by 65%) and serum glucose significantly lower (by 35%) in rats with a portacaval shunt. The lipid metabolism of epididymal adipose tissue was studied in vitro, as well as in vivo. In rats with a portacaval shunt, in vitro lipogenesis from [U-14C]glucose, [1-14C]acetate, or 3H2o was 60-80% lower than in sham-operated pair-fed controls. Twice as much in vitro basal lipolysis could be determined. In addition, in vivo lipogenesis from 3H2O was markedly decreased (6 times). By contrast, in rats with portacaval transposition, in vitro lipogenesis was higher (by 80-140%) and basal lipolysis lower (by 63%) than in pair-fed controls. Thus, even when the nutritional state was taken into consideration, the type of portal diversion was the determining factor in influencing lipid metabolism in epididymal adipose tissue.
The methods utilized in our laboratory for a biochemical approach of obesity include dietary manipulations, fatty acid analysis of tissue lipids, in vivo lipogenesis from [3H H2O and [1-14C] acetate, in vitro utilization of [3H] H2O, [U-14C] glucose, [U-14C] fructose, [U-14C] alanine and [1-14C] acetate by adipose tissue fragments, hormone sensitivity (to insulin and catecholamines), and the activity of enzymes such as fatty acid synthetase and adenylate cyclase in adipose tissue extracts. With these methods at hand, it is possible to estimate the major biochemical factors responsible for fat accumulation in adipose tissue. As an example, the case of obese (ob/ob) homozygotic animals of the C57BL/6J strain of Bar Harbor, which suffer from an autosomal recessive obese-hyperglycemic (O-H) syndrome, is compared to that of control nonobese (ob+/ob+) mice from the same strain. The hereditary O-H syndrome in ob/ob mice is characterized by obesity, resistance to the action of insulin, and hyperinsulinism. The development of obesity depends on high lipogenesis in fat depots. Contribute also to obesity a large influx of fatty acids of hepatic and dietary origin, and reduced lipolysis. In these mice, a high fat diet is more propitious to fat accretion than a high-carbohydrate diet.
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Glycerol release from epididymal fat fragments of young adult (3-month old) ob/ob mice was three times lower than normal, on a tissue weight basis. Dose-response curves in response to isoproterenol and ACTH-(1--24) indicated that the capacity of the lipolytic process was reduced. However, the sensitivity to both hormones was normal, i.e. greater for ACTH than for isoproterenol. The burst of cyclic AMP observed at 7 minutes was affected even more than the lipolytic capacity in adipose tissue from obese mice. This was already observed in 1-month old animals, i.e. at a time when total body weight was still normal. It is concluded that the adenylate cyclase system is defective in adipose tissue of ob/ob mice. Besides, glucagon, vasoactive intestinal polypeptide, and secretin failed to stimulate glycerol release and cyclic AMP accumulation in both ob/ob, ob+/ob+, and HA-ICR mice, suggesting that mouse adipose tissue does not possess receptors for this group of hormones.
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A new automated potentiometric method for the determination of colipase was developed, taking advantage of the reactivation of purified lipase, in the presence of bile salt and at pH 6.5. High-fat and high-starch diets induced an opposite regulation of lipase and amylase in the rat pancreas. At the same time, the level of colipase was not influenced by nutrition. During fasting and in alloxan diabetes, the specific activity of lipase almost doubled, that of amylase decreased sharply, and colipase was not affected in the rat pancreas. In obese-hyperglycemic mice, suffering from obesity, hyperinsulinism, and moderate diabetes, there was also no regulation of pancreatic colipase. Thus, at variance with a number of hydrolases, there was no dietary or hormonal adaptation of colipase. However, this was probably without any bearing on intraluminal lipolysis. Indeed, comparison of lipase and colipase activities in pancreas and in small intestine suggests that colipase concentration is not a limiting factor of intraluminal lipolysis. The molecular mechanism of this assumption is discussed on the basis of in vitro studies.
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Wheat germ agglutinin, but not concanavalin A or soybean lectin, inhibited the basal-and stimulated-adenylate cyclase activity which was present in a plasma membrane preparation from the rat pancreas. The inhibition by wheat germ agglutinin was rapid and sustained. It was of the non-competitive type and never exceeded 20% for Gpp (NH) p- and NaF-stimulated adenylate cyclase activity. The inhibition of secretin-stimulated activity was also non-competitive but more pronounced (57% inhibition at a wheat germ agglutinin concentration of 20 microgram/ml). For the C-terminal octapeptide of cholecystokinin-pancreozymin (OC-PZ)-stimulated cyclase, the inhibition amounted to 68% and was of a mixed type (both competitive and non-competitive). This last observation might be explained by the competitive inhibition exerted by wheat germ agglutinin on the binding of peptides of the OC-PZ family to their membrane specific receptors. The various inhibitory effects of wheat germ agglutinin were completely suppressed by incubating the membranes in the presence of ovomucoid, a N-acetyl-D-glucosamine rich glycoprotein. The possible functional implication of these results is discussed.