Cholecystokinin, amphetamine and diazepam and feeding in lean and obese Zucker rats.

The hyperphagia characteristic of some types of obesity may result from a deficiency in one or more components of the systems controlling satiety which in rats may include the gastrointestinal hormone cholecystokinin (CCK). Obesity may also influence responsivity to often used central nervous system (CNS)-acting drugs and combination of drugs. In these experiments it was shown that: (1) Zucker fatty rats were less sensitive than lean to intraperitoneal injections of 20 U/kg CCK after a 6-hr fast and when reduced were less sensitive than lean and less sensitive than when obese to injections of 5 U/kg CCK; (2) Although fatties were equally sensitive as leans to injections of 0.5 and 1.0 mg/kg d-amphetamine sulfate, when reduced, they were less sensitive; (3) Injections of 1.25 and 2.5 mg/kg diazepam produced smaller increases in food intake after a 6-hr fast in fatty and reduced fatty than lean rats; (4) Combination of diazepam with cholecystokinin in both fatty and lean rats produced feeding similar to that following injection of carrier; and (5) A similar additive effect was obtained in both fatty and lean rats when diazepam was combined with amphetamine; however, the fatty appeared to be more sensitive to the amphetamine than the diazepam effect. Thus the Zucker fatty rat appears to be less sensitive to these chemicals which affect food intake, which supports the contention that their CNS is generally less responsive.     

Amphetamines, growth hormone and narcolepsy.

1 Plasma amphetamine and growth hormone levels have been measured in eight normal and twenty-six narcoleptic subjects following a single dose of (+)-amphetamine (20 mg) or (-)-amphetamine (20 mg) by mouth. 2 Peak plasma levels and the shape of the plasma amphetamine-time curve were similar with both isomers in normal and narcoleptic subjects. 3 In most normal subjects both (+)-and (-)-amphetamine (20 mg) caused an increase in the plasma concentration of growth hormone. The two isomers were approximately equipotent in this respect. Neither (+)- nor (-)-amphetamine (20 mg) caused an increase in plasma growth hormone concentration in narcoleptics. 4 Following amphetamine (30 mg), two of six narcoleptic subjects had an increase in plasma growth hormone concentration. 5 Levodopa (250 mg) with (-)-alpha-methyldopa hydrazine 25 mg (Sinemet) by mouth, caused a rise in plasma growth hormone concentration in most normal subjects. The magnitude of the Sinemet-induced rise in plasma growth hormone concentration in narcoleptics was less than in normal subjects.     

Effect of fenfluramine on insulin/growth hormone ratio in obese subjects

Obesity is characterized by increased levels of insulin and by subnormal growth hormone (GH) release. Insulin/GH ratio is significantly higher in obese than in lean individuals. Fenfluramine, an anorectic drug, may have some effects on hypothalamic-pituitary function and on insulin secretion, possibly through a serotonergic stimulation. The aim of this work was to study the effects of fenfluramine on the insulin/GH ratio after arginine in obese subjects. Ten volunteer obese females were studied; 10 volunteer women were the normal weight controls. All subjects were given placebo and fenfluramine (60 mg p.o.) in a randomized order and after 120 min underwent arginine infusion (25 g i.v. for 30 min). Blood samples were taken every 30 min until 270 min for GH and insulin radioimmunoassay. In the obese group the GH response to arginine was significantly lower than in controls. Fenfluramine administration restored the subnormal GH response to arginine in obese subjects. Arginine infusion provoked a greater insulin secretion in obese subjects than in lean individuals. Fenfluramine administration diminished the insulin response to arginine. Fenfluramine did not modify the insulin/GH ratio in controls while it significantly lowered the insulin/GH ratio in obese subjects. Because insulin promotes fat and carbohydrate storage while GH stimulates lipolysis, the combination of high insulin and low GH concentrations may worsen the obese condition. A lower insulin/GH ratio can be useful in the treatment of obesity.     

Adipose tissue distribution and behaviour of selected gastro-entero-pancreatic hormones, glycaemia, growth hormone and somatomedin C in obese children

Twenty-three boys and 30 girls with simple obesity aged 12-16 years were investigated. The values of insulin, C-peptide, glycaemia, gastrinaemia and pancreatic polipeptide (PP) were measured in a fasting state and 30 and 60 min. after meal--at the beginning and after 3 weeks of reductive diet and physical exercise. The study of growth hormone and somatomedin C was deemed relevant to the issue in hand. Considerably higher insulinaemia and C-peptidemia values accompanied by impaired metabolic clearance of insulin and lowered glucose utilization in children with significant accumulation of adipose tissue in the abdominal area (waist/hip ratio p > 0.95), may constitute a possible predictor for diet-controlled diabetes mellitus and cardiovascular system diseases in adult age. Evaluation of adipose tissue in obese children makes it easier to indicate subjects exposed to complications at a later age. Low-caloric diet and physical exercise bring about a decrease in insulin secretion and an increase in its metabolic clearance. At the same time, glucose assimilation by cells is intensified.     

Individual variations in the effects of flurazepam,clorazepate, L-dopa and thyrotropin-releasing hormone on REM sleep in man

The influence of marijuana on the ability to perceive emotions in others was studied in 30 male volunteers who were experienced marijuana users. Subjects smoked either placebo or active marijuana containing 6 mg ⁹. The Affective Sensitivity Scale, a test developed to measure the ability to perceive emotions in others, was divided at midpoint and the two halves were administered before and after smoking, respectively. Analysis of variance demonstrated a decline in test scores following active marijuana administration, while changes following the placebo treatment were not significant.To whom offprint requests should be sent     

Pharmacokinetic/pharmacodynamic differentiation of pancreatic responsiveness in obese and lean children

OBJECTIVE: To determine the feasibility of differentiating the glucose-stimulated plasma insulin response between lean and obese children using a new PK/PD model that specifically considers the insulin-glucose physiology of beta cells. METHODS: Twenty four blood samples obtained after an intravenous bolus administration of glucose (250 mg/kg) were analysed for glucose and insulin concentrations in a group of six obese children, age 10.8 +/- 12.9 years (mean +/- CV%); BMI 26.7 +/- 27.8 kg/m(2), and six lean children, age 10.3 +/- 10.5, BMI 15.7 +/- 10.8. RESULTS: A PK/PD analysis of insulin concentration was performed and significant differences (p < 0.05) were determined from the parameters of our model in first and second phase insulin secretion between obese vs lean subjects. The estimated proinsulin formation rate constant was significantly higher in the obese group compared with the lean group (1.60 +/- 43.1 vs 0.378 +/- 40.9 min(-1)). The half-life of insulin in plasma was calculated to be 6.36 +/- 39.9 min for the obese group and 6.84 +/- 30.1 min for the lean group. The new model showed good agreement with data for both the obese group (r = 0.962 +/- 4.56) and for the lean group (r = 0.980 +/- 1.93). CONCLUSION: The proposed model is able to differentiate between lean and obese prepubertal children via specific kinetic parameters relating to beta-cell function.     

Effect of mevinolin on cholesterol metabolism in obese and lean Zucker rats

Mevinolin is a potent competitive inhibitor of HMG-CoA reductase, the enzyme catalyzing the major rate-limiting step in cholesterol synthesis. In this study the drug was administered as an intragastric dose at 2.5 mg/kg/day to 10 to 12-week-old lean and obese Zucker female rats over a 5-day period. Mevinolin showed no effect on plasma cholesterol levels in the lean rat; however, in the obese rat there was a significant decrease in plasma cholesterol (about a 40% decrease from initial levels). Although there was a difference in effect on plasma cholesterol levels in obese and lean rats, hepatocytes isolated from both fed lean and obese rats incubated with various concentrations of mevinolin exhibited similar levels of inhibition of cholesterol synthesis and showed no effects on the other metabolic processes studied. These results indicate that the drug was effective acutely on cholesterol synthesis in hepatocytes isolated from both lean and obese rats, but on a chronic treatment basis the hypocholesterolemic effect was observed only in the obese Zucker rat. This study supports the idea that the naturally occurring hypercholesterolemic obese Zucker rat may be a good model for testing potential new cholesterol lowering agents.     

Effects of acarbose on food intake,body weight and fat depots in lean and obese rats

Effects of dietary acarbose at 0, 5, 15 and 50 mg per 100 g diet on food intake and body weight were studied for two months in female rats. The relationships between diet composition, the drug dose and the type of obesity were examined. In lean rats receiving the drug in a high carbohydrate diet (70 Cal.%), mean food intake was similar to control at 5 and 15 mg dietary levels, but was significantly increased at 50 mg. Body weight was significantly reduced only at the 15 mg level. In VMH obese rats receiving the drug in a high carbohydrate diet, it resulted in significant reductions in food intake at the 15 and 50 mg drug levels and in significant reductions in body weight at all three drug levels. In dietary obese rats receiving the drug in a high carbohydrate diet and also in a 32% sucrose drinking solution, food intake and body weight were significantly reduced at each of the drug levels. In dietary obese rats receiving the drug in a high fat diet (70 Cal.%), acarbose at all levels resulted in only small and usually not significant changes in either food intake or body weight. Weight of fat depots were significantly reduced at the 50 mg dietary level in all instances where a high carbohydrate diet was used while at the 5 mg level, fat depots were reduced only in the VMH obese, with the sucrose obese showing a trend for reduced depots. Acarbose in the high fat diet resulted in no significant changes in weight of fat depots. These data indicate that acarbose in a high carbohydrate diet is effective in reducing weight of rats, and that obese usually show a greater reduction in food intake and body weight than lean rats.     

Plasma bromocriptine levels, clinical and growth hormone responses in Parkinsonism.

1. Plasma bromocriptine levels following separate oral doses of bromocriptine 12.5, 25, 50 and 100 mg have been determined in ten subjects with parkinsonism. 2. There was considerable variation between peak plasma bromocriptine levels in individual subjects after similar doses of bromocriptine. Peak levels occurred 30--210 min after dosage (mean 102 min). Peak clinical response, peak rise in plasma growth hormone level and fall in blood pressure followed shortly after peak bromocriptine levels occurred. 3. The shape of the plasma-time curve for bromocriptine was similar with all dosages. 4. There was no significant relationship between peak plasma bromocriptine levels, peak clinical response, peak increase in growth hormone and peak fall in blood pressure. However, the degree of improvement in the signs of parkinsonism was related to plasma bromocriptine levels was achieved. 5. Metoclopramide 60 mg pretreatment had no consistent effect upon plasma bromocriptine levels, the clinical or hormonal response.     

Opioid-induced linear running in obese (ob/ob) and lean mice

Earlier research has shown that opioids stimulate behavioral activation in mice whereas opioid antagonists attenuate this activation. We conducted an experiment to determine the dose-response curve of FK33824, a potent Met-enkephalin analogue. FK33824 produced an unusual form of behavioral activation we called "linear running" in which the mice ran continuously in one direction and were nearly oblivious to environmental stimuli. This may be the kind of running that occurs naturally during migration. Wheel running activity of genetically obese (ob/ob) and lean (C57BL/6J ?/+) mice was measured following the intracerebroventricular infusion of 0.1, 1.0, 10.0 and 100.0 ng of FK33824. The lowest dose did not alter baseline running, whereas the 1.0 and 10.0 ng doses significantly increased running in both genotypes. We found a genotype difference with the highest dose tested, the lean mice ran at baseline levles and displayed ataxia whereas the obese mice continued to show increased running without ataxia. We hypothesize that genetic differences in the enkephalin mechanisms of C57 lean and obese mice are responsible for linear running.     

左旋多巴激发试验在生长发育迟缓儿童中的临床价值

目的探讨左旋多巴激发试验在生长发育迟缓儿童中的临床价值。方法对生长发育迟缓儿童采用左旋多巴激发试验,生长激素测定采用化学发光法。结果(1)生长激素的峰值在左旋多巴激发后30和60 m in出现最多(P<0.01);(2)生长激素完全缺乏者占29.8%,部分缺乏占55.3%,而完全不缺乏者仅占14.9%。结论儿童生长发育迟缓大多数是由于生长激素缺乏或部分缺乏所致。左旋多巴激发试验可作为临床诊断侏儒症的方法之一。     

Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice.

Although originally developed as an antidepressant, long-term bupropion (BUP) treatment was recently shown to cause 5-8% weight loss over placebo in clinical trials with obese adults. BUP's antidepressant properties probably stem from its ability to increase extracellular brain dopamine (DA) and norepinephrine (NE) levels by inhibiting their reuptake, although the mechanism of BUP-induced weight loss is unknown. Consequently, the acute effects of DA and NE reuptake inhibition on energy homeostasis were determined by measuring food intake and body weight in mice following peripheral (intraperitoneal (i.p.)) administration of either BUP, a selective DA (GBR12783), or a selective NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via mini-osmotic pump) administration of GBR12783 and NIS produced a transient nonadditive effect on food intake, but produced an additive reduction in body weight (8-10%). Because obesity can affect catecholaminergic signaling, we determined the effects of i.p. BUP, GBR12783, and NIS on short-term food intake in obese mice. Acute BUP, GBR12783, and NIS dose-dependently reduced acute food intake, and the additive effect of GBR12783 and NIS on acute food intake was preserved in obese mice. These results demonstrate that combined DA and NE reuptake inhibition produces additive effects on energy balance in lean and obese mice on both standard and high-fat diet, providing a foundation for further research on the effects of BUP and similar compounds on energy balance in mice.     

Fenfluramine discrimination in obese and lean Zucker rats: serotonergic mediation of effect

Genetically obese Zucker rats and their lean littermates were trained to discriminate between the stimulus properties of 2.0 mg/kg fenfluramine and its vehicle in a two-lever, food-motivated operant task. Both groups learned the discrimination at the same rate and all rats showed a dose-related decrease in discriminative performance with lower fenfluramine doses. Analysis of the dose-response curves indicated an ED50 for the obese rats of 0.56 mg/kg and for the lean group of 0.42 mg/kg. Time-course experiments indicted that the obese rats maintain errorless discrimination through 90 min post-injection but discriminate significantly less than the lean rats at 960 min post-administration. These results suggest a similar sensitivity to fenfluramine in obese and lean rats with a difference in the time-course of drug action. Pre-treatment with the specific serotonin receptor antagonist pirenperone significantly attenuated fenfluramine discrimination in lean rats without a similar effect in the obese rats. Possible reasons for this observation are offered.     

The effects of obesity and exercise on the pharmacokinetics of caffeine in lean and obese volunteers

Summary The effects of obesity, exercise, and the interaction of obesity and exercise were examined in 6 caffeine naive, untrained, nonsmoking, college males (3 lean (LV), 3 obese (OV)). Each subject received caffeine (oral, 5.83 mg·kg^–1 lean body weight) or placebo (50 mg citrate) prior to 3 h of seated rest and prior to 90 min of treadmill walking (40% of their maximal aerobic power) followed by 90 min of seated recovery. Serum samples were collected at various times and analyzed for caffeine by HPLC. Pharmacokinetic analysis indicated that at rest, OV had a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397 min^–1), lower elimination rate constant (Ke 0.0027 vs. 0.0045 min^–1), and longer serum half-life (t_1/2 4.37 vs. 2.59 h) in comparison to LV. In exercise, as well as at rest LV and OV had a large difference in the volume of distribution (43.2 vs. 101. 1) (rest, 54.1 vs. 103.1). Exercise consistently resulted in a decrease in the maximal serum concentration of caffeine and the area under the curve in OV while having no consistent effect on LV. The interactive effects of obesity and exercise could not be dissociated. However, these results demonstrate that both obesity and exercise have modified the pharmacokinetics of caffeine.This work was presented at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics, Boston, August 22, 1985     

Ciprofibrate, clofibric acid and respective glycinate derivatives. Effects of a four-week treatment on male lean and obese Zucker rats

Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over ciprofibrate or clofibric acid.     

Biliary lipids, cholesterol and bile synthesis: different adaptive mechanisms to dietary cholesterol in lean and obese subjects

BACKGROUND: Increased biliary cholesterol secretion together with elevated cholesterol synthesis may predispose obese subjects to cholesterol gallstone formation. AIM: To investigate whether processing of dietary cholesterol is altered in obesity, we enrolled eight lean and seven obese subjects in a double-blind crossover study. METHODS: Cholesterol consumption was 300 mg/day on low and 1300 mg/day on high cholesterol diet. After 3 weeks on either diet, hepatic bile was collected to determine biliary lipid secretion, and bile salt composition by high-performance liquid chromatography and cholesterol saturation index was calculated. Cholesterol synthesis was measured employing mass isotopomer distribution analysis. Bile acid synthesis via neutral and acidic pathway was assessed by serum levels of 7alpha-hydroxy-4-cholesten-3-one and 27-hydroxycholesterol. RESULTS: Cholesterol synthesis was increased in obese compared with lean and feedback inhibited only in obese. On low cholesterol diet, cholesterol secretion was doubled in obese but bile acid composition and synthesis was similar between the two groups. After high cholesterol diet, cholesterol saturation index and bile secretion were unchanged. In contrast to obese, lean increased bile acid synthesis only via the acidic pathway. CONCLUSIONS: Dietary cholesterol appears to preferentially induce bile acid synthesis via the acidic pathway in lean, whereas cholesterol synthesis was inhibited in obese. Thus, stable cholesterol saturation index may be achieved by different mechanisms.     

Elephant growth hormone. Isolation and characterization

Growth hormone has been purified to homogeneity from elephant pituitary glands. It has 191 amino acids with two disulfide bridges and a single tryptophan residue. The somatotropin activity is only 15% when compared with the bovine hormone in the radioreceptor binding assay. From circular dichroism spectra α-helical content of elephant growth hormone is estimated to be 50%. Difference absorption spectra of the hormone suggest the presence of a hydrogen bond between the single Trp and a carboxylate ion.