Carol L. McLaughlin

Obese mice and the satiety effects of cholecystokinin, bombesin and pancreatic polypeptide.

Abstract Cholecystokinin (CCK-8), bombesin (BBS) and pancreatic polypeptide (PP) are gastrointestinal hormones which are released during a meal and which decrease food intake when administered exogenously. The satiety effects of CCK-8, BBS and PP were measured in weanling and adult Bar Harbor obese and lean mice. Weanling mice fasted 5.5 hr were less sensitive to both CCK-8 and BBS at 5–6 weeks of age, when body weights of the obese were 20% greater than lean. The obese were equally sensitive as lean mice to CCK-8 and BBS at 7–8 weeks of age when the obese were 50% heavier. After a 3.0 hr fast adult obese mice, weighing 100% more than lean mice, were less sensitive to satiety effects of lower doses of CCK-8 (1.0 μg/kg) and PP (8 μg/kg) but equally sensitive to higher doses of CCK-8 (2.0 μg/kg), PP (16 μg/kg) and all doses of BBS (2.0, 4.0 and 8.0 μg/kg). After a 6-hr fast, 16 μg/kg PP did not affect food intake in obese or lean mice, whereas 32 μg/kg PP decreased food intake more in obese than lean mice. Thus both weanling and adult obese mice, as obese rats, are less sensitive to the putative satiety agent CCK-8.

Decreased sensitivity of Zucker obese rats to the putative satiety agent cholecystokinin.

Abstract In obese rodents increased daily food intake leading to accumulation of adipose tissue is frequently accompanied by increased meal size and loss of the normal diurnal variations in feeding pattern. Increased meal size of obese rats may be due to decreased sensitivity to factors which elicit satiety. We compared Zucker obese and lean rat feeding behavior responses to octapeptide of cholecystokinin (OP-CCK), a peptide shown to decrease meal size in several species. Obese rats were less sensitive than lean rats to OP-CCK (.06, .25 and 1.0 μg/kg/meal) injected before each of four consecutive scheduled meals in the light portion of the diurnal cycle, when obese meal size was larger than lean. However, neither obese nor lean rats responded to injection of the same doses of OP-CCK during meals in the dark, when average meal size was larger than during the light and when average meal size of the obese rats was similar to that of lean rats. In both obese and lean rats injection of OP-CCK affected daily feeding pattern. Obese and lean Zucker rats are less sensitive to OP-CCK when meal size is larger, whether this is due to phase of the diurnal cycle (dark vs. light in both obese and lean rats) or phenotype (obese vs. lean rats in the light).

Opiate antagonists and agonists and feeding in sheep

Abstract Recent evidence indicates that endogenous opiate peptides may be involved in the control of food intake. In previous experiments, injection of β-endorphin has stimulated food intake and peripheral injections of the opiate antagonist, naloxone, decreased food intake in rats. In the present experiments, food and water intakes of sheep were measured in response to peripherally administered opiate antagonists and continuous lateral ventricular administration of opiate agonists. Intravenous injections of both of the opiate antagonists naloxone (0.03, 0.062 and 0.125 mg/kg) and 3–4(hydroxyl-phenyl)-3-4-dimethyl-piperidine propiophenone maleate (0.03, 0.062 and 0.125 mg/kg) decreased food intake for up to 90 min in 4-hr fasted sheep. In water-deprived sheep, naloxone did not affect water intake or body temperature for the first 4 hr but depressed 24 hr water intake. Continuous 90-min injection of 26, 51 and 102 nmoles/min of the opiate agonist D-ala 2 -met-enkephalinamide (DME) increased food intake of satiated sheep. Intravenous injection of 0.125 mg/kg naloxone blocked the increase in food intake elicited by intraventricular injection of DME. In contrast, intraventricular injection of kyotorphin, a releasor of endogenous enkephalin in the brain, did not affect food intake. Thus, in sheep intracerebroventricular administration of opiate agonists increased food intake; peripheral administration of opiate antagonists decreased food intake and blocked the feeding induced by agonists.

Oral and hypothalamic injections of barbiturates, benzodiazepines and cannabinoids and food intake in rats ☆

To evaluate and compare CNS sites of action of chemicals which stimulate feeding, intakes were measured after ventromedial hypothalamic (VMH) and lateral hypothalamic (LH) administration of pentobarbital sodium (PBS), diazepam (D) and the d- and l-isomers of Δ9-tetrahydrocannabinol (THC); and intragastric administration of D and d- and 1-THC. In rats fed ad lib PBS (8 and 16 μg) increased intake tenfold (p<0.05) 0.5 hr after injection in the VMH, but not the LH. Intragastric administration of 2.5 and 5 mg/kg D increased intake twofold (p<0.01) at 0.5 and 2 hr but did not affect 24 hr intake. VMH injections of D (10 and 20 μg) caused a 15-fold increase (p<0.05) at 0.5 but not 24 hr, but LH injection of D did not affect 0.5 or 24 hr intake. Intragastric administration of 4 mg/kg 1-THC increased (p<0.01) food intake at 1 and 2 hr, but 24 hr intake was not affected; d-THC had no effect. VMH, but not LH, injection of 1-THC (0.25 μg) caused a 24-hr increase in intake. d-THC (0.25 μg) caused a decrease (p<0.05) in feeding at 0.5 hr, but not 24 hr when administered in the VMH, and increased (p<0.05) feeding at 24 hr when injected in the LH. The VMH appears to mediate the action of both PBS and D, but the increased feeding caused by systemic 1-THC is not duplicated by VMH administration, thereby suggesting an alternate site of action.

Nalmefene decreases meal size, food and water intake and weight gain in Zucker rats

Opioids are proposed to play a role in the control of food intake since administration of opioids increase food intake while administration of opioid antagonists decrease food intake. In these experiments responses to a new opioid antagonist, nalmefene, were measured in Zucker obese and lean rats. In obese male rats 1 mg/kg nalmefene decreased the size of the first meal after a 10-hr fast and decreased 14-hr food intake, indicating nalmefene is relatively long-acting. Administration of 1 mg/kg nalmefene daily for 7 days decreased average meal size and daily food intake and increased meal frequency; feeding responses on day 7 were similar to those on day 1, suggesting a lack of development of tolerance. Food and water intake and weight gain during a 3-week treatment period were decreased more in lean rats by low doses of nalmefene (up to 0.25 mg/kg) and more in obese rats by higher doses of nalmefene (0.50 mg/kg). These responses to a new opioid antagonist further support a possible role for opioids in the control of food intake.

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.

Meal-stimulated increased concentrations of CCK in the hypothalamus of Zucker obese and lean rats.

CCK is a putative satiety peptide found to be active when administered peripherally and centrally. Concentrations of CCK have been measured in the brains of fed and fasted animals, but as yet no clear correlation with feeding has been found. In the present experiment rats were sacrificed after a 6-hr fast or 5 min after a meal. Areas of the hypothalamus were removed from these rats and assayed for CCK content. The relationship between obesity and CCK content in specific areas of the brain was also investigated by using Zucker obese and lean rats. In fed rats the CCK concentrations were higher than in fasted rats in the ventromedial hypothalamus (VMH) (56 vs. 42 pg/mg tissue, p less than 0.005), lateral hypothalamus (38 vs. 27 pg/mg, p less than 0.01) and supraoptic nucleus (48 vs. 39 pg/mg, p less than 0.01). In obese rats the concentrations were higher than in lean rats in the VMH (56 vs. 41 pg/mg, p less than 0.003), dorsal medial hypothalamus (37 vs. 30 pg/mg, p less than 0.04) and anterior hypothalamus (61 vs. 37 pg/mg, p less than 0.001). Average concentrations of CCK in all hypothalamic areas were higher in females than males (50 vs. 40 pg/mg, p less than 0.001). Thus, CCK concentrations in specific areas of the hypothalamus increased with feeding, supporting the potential role of CCK in the central nervous system as a satiety peptide. Further, although the concentrations of CCK in obese rats were higher than those in lean rats, the changes in CCK concentration with feeding were the same, showing that obesity is not a consequence of decreased concentrations or concentration changes of CCK in brain.

Feeding response of weanling Zucker obese rats to cholecystokinin and bombesin.

Abstract Zucker weanling obese rat meal size is greater than in lean litter-mates by 4 weeks of age, indicating a possible decreased sensitivity to satiety signals. Adult Zucker obese rats are less sensitive to the putative satiety signal octapeptide of cholecystokinin (OP-CCK) when injected after a normal intermeal interval. In these experiments were compared responses of Zucker lean and obese rats from 3–11 weeks of age to OP-CCK and bombesin (BBS), another recently reported putative satiety agent. Injection of 2.0 and 4.0 μg/kg OP-CCK in 4–5 week olds had no effect on food intake of obese rats while decreasing 60-min food intake in lean rats 29 and 28 percent, respectively. However, 8.0 μg/kg OP-CCK decreased food intake of obese and lean rats similarly, indicating decreased, rather than lack of, sensitivity in the obese. The doses of 2.0 and 4.0 μg/kg BBS decreased food intake similarly in the obese and lean rats, but 1.0 μg/kg, although having no effect in lean rats, increased food intake in obese rats approximately 17 percent. Thus, while Zucker obese weanling rats appear to be less sensitive to OP-CCK, shown to decrease food intake in lean rats, they appear to be equally sensitive to the satiety effect of similar doses of BBS, but at low doses BBS stimulated food intake in obese but not lean rats.

Effect of CCK antibodies on food intake and weight gain in zucker rats

While exogenous administration of cholecystokinin (CCK) decreases food intake in many species, it has not been demonstrated conclusively that CCK is necessary for satiety to occur. In these experiments the role of CCK in eliciting satiety was further investigated by using endogenously produced and exogenously administered antibodies to CCK which were hypothesized to sequester circulating CCK. In the first experiment Zucker obese (n = 12, 192 +/- 16 g) and lean (n = 12, 152 +/- 11 g) male rats were administered CCK-8 conjugated to bovine serum albumin or bovine serum albumin by subcutaneous administration in Freunds adjuvant. Average percent binding of 125I-gastrin-17 by serum taken 4, 8 and 12 weeks after treatment initiation was increased (19.9 vs. 2.1, p less than 0.001) in rats treated with CCK conjugate than controls, and the increase was greater in lean (27.5 vs. 1.9) than in obese (12.2 vs. 2.2, p less than 0.001) rats. In lean, but not obese rats, average daily food intake and weight gain were increased (9 and 17% p less than 0.04 and p less than 0.02 respectively) in rats with CCK-AB compared with rats with no CCK-AB during the three months. Development of CCK-AB did not affect food intake response to exogenously administered CCK-8 or pancreas weight relative to body weight. In Experiment 2 increased food intakes of obese and lean rats 30 min after intraperitoneal injection of rabbit serum with CCK-AB were greater than those after intraperitoneal injection of rabbit serum without CCK-AB (1.92 vs. 1.41, g, p less than 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

Feeding behavior responses of Zucker rats to naloxone

The effects of naloxone on feeding patterns were studied in both obese and lean Zucker rats during both light and dark phases of the diurnal cycle. Eight female obese (471 +/- 9 g) and lean (225 +/- 6 g) Zucker rats were trained to bar press for food. They were administered 0, 0.5, 1.0 or 2.0 mg/kg naloxone at the initiation of the light or dark phase of the diurnal cycle and feeding behavior was recorded for the subsequent 12 hr using an automated real-time data collection system. First meal size and duration were decreased and first postmeal interval was increased by naloxone and responses did not vary with phenotype or phase of the diurnal cycle. Naloxone decreased food intake during the 12-hr period by decreasing average meal size but meal frequency was not affected. Overall, the feeding behavior responses of obese rats to naloxone were greater than those of lean rats, supporting the hypothesis of an association between opioid peptides and obesity. Opioid involvement in diurnal control of food intake is also supported by the greater responses generally demonstrated in the light compared with dark phases.