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F Rohner-Jeanrenaud,
L S Craft,
J Bridwell,
T M Suter, F C Tinsley,
D L Smiley,
D R Burkhart,
M A Statnick,
M L Heiman,
E Ravussin,
J F Caro
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ABSTRACT: Cocaine- and amphetamine-regulated transcript (CART) is expressed within hypothalamic nuclei implicated in the regulation of feeding behaviour. It is up-regulated by leptin, and CART-derived peptides acutely inhibit food intake.
The present study was designed to assess the long-term effects of central CART administration on food intake, body weight, plasma levels of glucose, insulin, leptin, free fatty acids and triglycerides, and on fuel utilisation in normal and high-fat-fed obese rats.
Normal and high-fat-fed obese rats were cannulated intracerebroventricularly (i.c.v.) and infused for 6 days with CART (55-102) or its vehicle. At day 4, animals were placed in an indirect calorimeter for a 24 h period during which the respiratory quotient and the energy expenditure were determined hourly.
In both normal and obese animals, the chronic i.c.v. infusion of CART (55-102) had marked, sustained inhibitory effects on food intake and body weight gain that were accompanied by decreases in plasma insulin and leptin levels. Using indirect calorimetry, it was observed that CART infusion promoted an increase in lipid oxidation in normal and in obese animals, although this increase reached statistical significance only in the obese group. The hypothalamic CART mRNA expression was found to be higher in obese rats (displaying hyperleptinaemia) than in normal animals.
The data together show that chronic i.c.v. CART infusion is effective in inhibiting food intake, favouring lipid oxidation and limiting fat storage, both in normal and high-fat-diet-induced obese rats. The CART pathway thus seems to be an important determinant of body weight homeostasis in normal animals as well as in a model of nutritionally induced obesity.
International Journal of Obesity 03/2002; 26(2):143-9. · 4.69 Impact Factor
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ABSTRACT: Two competitive particle concentration fluorescence immunoassays were developed to measure blood levels of analogs of anti-diabetic drugs being tested in diabetic mice. Ligands that contained the active pharmacophores were conjugated to PPD for immunization and to beta-phycoerythrin for use as a tracer in the immunoassays. Approximately 90% of 262 compounds assayed were detectable at less than 120 nM in plasma which was well below the estimated therapeutic level of 1 microM for lowering blood glucose. These data were used to define the bioavailability of test compounds and assist in decisions of constructing active analogs. Of additional interest, we noted crossreactivity of one monoclonal antibody for 3 different compound classes that are all known to bind with varying affinities to peroxisome proliferator-activated receptors.
Journal of Immunological Methods 09/1997; 207(1):23-31. · 2.20 Impact Factor
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ABSTRACT: Monoclonal antibodies (MoAbs) were made to a known insulin sensitivity enhancer (ISE) compound, CS-045. The MoAbs were characterized with respect to binding other known thiazolidinedione ISE compounds using a CS-045 labeled with b-phycoerythrin in a competitive particle concentration fluorescence immunoassay (PCFIA). By comparing the rank order of IC50 values for each compound to its respective potency as an ISE, one MoAb (13E3) was selected for further characterization. This MoAb was also used as a surrogate receptor in a high throughput screen to identify novel compounds that compete for binding to CS-045. Some of the hits were found to have efficacy in reducing blood glucose. Subsequently, another group reported that several compounds with the core thiazolidinedione structure of the ISE compounds bound with high affinity to peroxisome proliferator-activating receptors (PPAR). Therefore, we used the MoAb assay to test these and other compounds that are known to bind to PPARgamma and noted crossreactivity with some of the compounds.
Life Sciences 02/1997; 61(23):2305-15. · 2.53 Impact Factor
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ABSTRACT: A new orally active histamine H2-receptor antagonist, nizatidine (LY139037), was evaluated in male rats for effects on mechanisms regulating accessory sex organ growth and function. Cimetidine antagonized androgen binding to cytosolic receptors in vitro while nizatidine had no effect. Nizatidine and cimetidine were administered at the ED50, 5 X ED50, or 10 X ED50 doses for inhibition of gastric acid secretion previously determined using in vivo dog and rat models. The relative potencies of both agents to antagonize histamine H2-receptor-mediated gastric acid secretory responses have been confirmed in human clinical trials. Neither nizatidine nor cimetidine antagonized the in vivo uptake or nuclear translocation of radiolabeled androgen into the hypothalamic-preoptic-amygdala, pituitary, or ventral prostate. Nizatidine, given at doses equal to and 10 X the ED50 gastric acid secretion inhibitory values, and cimetidine (10 X ED50 value) had no effect on the response of male accessory sex organs to a submaximally stimulating dose of androgen in castrated rats. High doses of dietary nizatidine (greater than 500 mg/kg-day) administered for 6 months did not alter intact rat male accessory sex organ weights or circulating androgen levels relative to untreated controls. Acute administration of either nizatidine or cimetidine produced transient elevations in plasma prolactin (PRL) levels. Cimetidine was more potent and consistent than nizatidine in producing these increases in circulating PRL. The data described herein support the contention that unlike cimetidine, nizatidine is not a pharmacological antagonist of androgen action and has less of a stimulatory effect upon plasma prolactin. Taken together, these studies indicate that in the male rat, nizatidine exhibits a large therapeutic index between its gastric antisecretory activity and potential endocrinological effects.
Toxicology and Applied Pharmacology 03/1990; 102(2):219-32. · 4.45 Impact Factor
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ABSTRACT: Sustained subcutaneous administration of recombinant DNA-derived insulin-like growth factor II to immature female hypophysectomized rats stimulated significant increases in body weight gain, tibial epiphyseal cartilage width, femur hydroxyproline concentrations and a significant decrease in serum urea nitrogen concentrations. Recombinant DNA-derived human growth hormone (Humatrope), administered in the same manner produced similar biological effects. The data support the contention that hIGF-II has anabolic effects when administered to hypophysectomized rats and may be a locally acting mediator of pituitary hormone actions.
Endocrine Research 02/1989; 15(3):403-11. · 0.97 Impact Factor
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ABSTRACT: The 20,000 dalton variant of recombinant DNA-derived methionyl human growth hormone (20K-Met-hGH) induced decreases in blood glucose and free fatty acid concentrations one hour after intraperitoneal injection into fasted, hypophysectomized rats. Similar results were obtained using the 22,000 dalton form of recombinant DNA-derived methionyl human growth hormone (22K-Met-hGH). The data reported show that 20K-Met-hGH induces early insulin-like effects similar to the responses produced by 22K-Met-hGH in fasted hypophysectomized rats.
Biochemical and Biophysical Research Communications 08/1986; 138(1):342-8. · 2.48 Impact Factor
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ABSTRACT: The recombinant DNA-derived 20,000-dalton variant of N-terminal methionyl human growth hormone (20K-Met-hGH) had a hyperglycemic effect in fasted dogs when injected 11 hours prior to an oral glucose tolerance test (OGTT). These results reported here suggest that 20K-Met-hGH can induce glucose intolerance in dogs similar to that produced by recombinant DNA-derived 22,000 dalton N-terminal methionyl human growth hormone (22K-Met-hGH) and the normal pituitary-source human growth hormone (22K-hGH).
Endocrine Research 02/1986; 12(1):21-35. · 0.97 Impact Factor
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ABSTRACT: A method for preparation and surgical implantation of a rodent jugular vein cannula and construction and use of an automatic blood-sampling system are described. The cannula permits repeated blood sampling without disturbing the rat. The semiautomatic sampling system permits one individual to collect blood samples from three rats simultaneously.
Journal of applied physiology: respiratory, environmental and exercise physiology 06/1983; 54(5):1422-6. · 3.73 Impact Factor
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ABSTRACT: Pseudopregnant and cyclic rats were injected for 5 to 26 days with daily doses of 5 and/or 3 mg of 5-bromo-2-thienyl-ethyl-ketone thiosemicarbazone (70026) starting on Day 0 (the day of oestrus). The vaginal smear cytology, record of ovulation and ability to breed and conceive were compared with the results for corn oil-injected controls. Both doses of 70026 were found to cause a reappearance of pro-oestrous and/or oestrous vaginal smears within 4 to 6 days in the pseudopregnant rats, but ovulations did not occur. The 5-mg dose of 70026 inhibited ovulation and interrupted the oestrous cycle in cyclic rats, even though the daily 3-mg dose seemed to have little effect on ovulation, ovarian cyclicity, breeding or conception. In spite of the absence of an ovulation accompanying the induced pro-oestrous and/or oestrous vaginal smears in the pseudopregnant rats, the pattern of the vaginal smears suggested the occurrence of a 'delayed pseudopregnancy' in most of the pseudopregnant rats treated daily with 3 mg, but in few of those treated with 5 mg, 70026.
J Reprod Fertil 10/1975; 44(3):421-8.
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J Reprod Fertil 04/1970; 21(2):233-41.
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Endocrinology 12/1969; 85(5):831-6. · 4.46 Impact Factor
