sincalide and Hyperphagia

Bacterially derived factors are implicated in the causation and persistence of obesity. Ingestion of a high fat diet in rodents and obesity in human subjects is associated with chronic elevation of low plasma levels of lipopolysaccharide (LPS), a breakdown product of Gram-negative bacteria. The terminals of vagal afferent neurons are positioned within the gut mucosa to convey information from the gut to the brain to regulate food intake and are responsive to LPS. We hypothesized that chronic elevation of LPS could alter vagal afferent signaling. We surgically implanted osmotic mini-pumps that delivered a constant, low-dose of LPS into the intraperitoneal cavity of rats (12.5 μg/kg/hr for 6 weeks). LPS-treated rats developed hyperphagia and showed marked changes in vagal afferent neuron function. Chronic LPS treatment reduced vagal afferent leptin signaling, characterized by a decrease in leptin-induced STAT3 phosphorylation. In addition, LPS treatment decreased cholecystokinin-induced satiety. There was no alteration in leptin signaling in the hypothalamus. These findings offer a mechanism by which a change in gut microflora can promote hyperphagia, possibly leading to obesity.

Topics: Animals; Blotting, Western; Eating; Hyperphagia; Immunohistochemistry; Leptin; Lipopolysaccharides; Male; Neurons, Afferent; Nodose Ganglion; Peroxidase; Rats, Wistar; Satiation; Sincalide; Weight Gain

Corticotropin-releasing factor (CRF) overexpressing (OE) mice are a genetic model that exhibits features of chronic stress. We investigated whether the adaptive feeding response to a hypocaloric challenge induced by food deprivation is impaired under conditions of chronic CRF overproduction. Food intake response to a 16-h overnight fast and ip injection of gut hormones regulating food intake were compared in CRF-OE and wild type (WT) littermate mice along with brain Fos expression, circulating ghrelin levels, and gastric emptying of a nonnutrient meal. CRF-OE mice injected ip with saline showed a 47 and 44% reduction of 30-min and 4-h cumulative food intake response to an overnight fast, respectively, compared with WT. However, the 30-min food intake decrease induced by ip cholecystokinin (3 microg/kg) and increase by ghrelin (300 microg/kg) were similar in CRF-OE and WT mice. Overnight fasting increased the plasma total ghrelin to similar levels in CRF-OE and WT mice, although CRF-OE mice had a 2-fold reduction of nonfasting ghrelin levels. The number of Fos-immunoreactive cells induced by fasting in the arcuate nucleus was reduced by 5.9-fold in CRF-OE compared with WT mice whereas no significant changes were observed in other hypothalamic nuclei. In contrast, fasted CRF-OE mice displayed a 5.6-fold increase in Fos-immunoreactive cell number in the dorsal motor nucleus of the vagus nerve and a 34% increase in 20-min gastric emptying. These findings indicate that sustained overproduction of hypothalamic CRF in mice interferes with fasting-induced activation of arcuate nucleus neurons and the related hyperphagic response.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Cholecystokinin; Corticotropin-Releasing Hormone; Eating; Energy Intake; Fasting; Gastric Emptying; Gene Expression Regulation; Genes, fos; Ghrelin; Hyperphagia; Hypothalamus, Middle; Mice; Neurons; Nootropic Agents; Sincalide

The influence of cholecystokinin octapeptide (CCK-8) on normal and insulin-induced feeding and expression of orexigenic hypothalamic neuropeptides was investigated in male rats. CCK-8, administered during meals (4 microg/kg) or continuously (32 microg/kg over 60 min), blunted the stimulating effect of insulin (50 IU/kg) on feeding by reducing meal size (-60%; P<0.05 or -86%; P<0.0001, respectively). Rats without access to food and injected with IP insulin (50 IU/kg) showed increased hypothalamic mRNA levels of orexin (+30%; P<0.05) and melanin-concentrating hormone (+52%; P<0.05), as compared with ad libitum-fed and saline-injected control rats. Continuous IP infusion of CCK-8 (32 microg/kg) blunted these increases. Our results suggest that both orexin and melanin-concentrating hormone participate in the response to insulin hypoglycemia without food being present; these neurons may be involved in mechanisms related to insulin-induced hyperphagia. Signals triggered by peripheral CCK-8 act to decrease the expression of orexin and melanin-concentrating hormone. This may be associated with a reduction in hyperphagia.

Topics: Animals; Blood Glucose; Feeding Behavior; Hyperphagia; Hypoglycemia; Hypothalamic Hormones; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Male; Melanins; Neuropeptides; Orexins; Pituitary Hormones; Rats; Rats, Sprague-Dawley; RNA, Messenger; Satiety Response; Sincalide; Time Factors

In mammals, including humans, a brain-gut hormone, cholecystokinin (CCK) mediates the satiety effect via CCK-A receptor (R). We generated CCK-AR gene-deficient (-/-) mice and found that the daily food intake, energy expenditure, and gastric emptying of a liquid meal did not change compared with those of wild-type mice. Because CCK-AR(-/-) mice show anxiolytic status, we examined the effects of restraint stress. Seven hours of restraint stress was found to significantly decrease both body weight and food intake during the subsequent 3 days in all tested animals. On the fourth day after restraint stress, the CCK-AR(-/-) mice showed a significantly higher level of daily food intake than prior to stress, and food intake recovered to prestress levels in the wild-type mice. Since peripheral CCK-AR has been known to mediate gastric emptying, both gastric emptying and gastric acid secretion were determined to examine the mechanism of overeating in CCK-AR(-/-) mice. Neither gastric emptying nor gastric acid secretion differed between CCK-AR(-/-) and wild-type mice on the fourth day after stress. In contrast, however, the contents of dopamine and its metabolites in the cerebral cortex of CCK-AR(-/-) mice were increased by stress, but were rather decreased in wild-type mice. Changes in 5-hydroxytryptamine (5-HT) and its metabolite 5HIAA did not differ between the genotypes. In conclusion, CCK-AR(-/-) mice showed overeating after restraint stress, and dopaminergic hyperfunction in the brain of these mice was observed. The present evidence suggests that the CCK-AR function, possibly via altering the dopaminergic function, might be involved in overeating after stress.

Topics: Animals; Body Weight; Cholecystokinin; Eating; Gastric Acid; Gastric Emptying; Hormone Antagonists; Humans; Hyperphagia; Mice; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Sincalide

This work expands recent observations that Otsuka Long-Evans Tokushima Fatty (OLETF) rats show little or no pancreatic expression of the cholecystokinin (CCK)-A receptor gene. We examined whether the CCK-A and -B receptor genes were expressed in the brain (hypothalamus) of OLETF rats in comparison with control (Long-Evans Tokushima Otsuka = LETO) rats. CCK-A receptor mRNA was detected in the hypothalamus of LETO rats but not OLETF rats. The CCK-B receptor gene was expressed in the hypothalamus in both strains. Cerebroventricular administration of CCK-8 sulfate inhibited daily food intake in LETO rats, but not in OLETF rats. These results show that in OLETF rats the absence of CCK-A receptor gene expression in the hypothalamus results in hyperphagia because of lack of satiety.

Topics: Animals; Base Sequence; Cholecystokinin; Diabetes Insipidus; Hyperphagia; Hypothalamus; Male; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Rats; Rats, Mutant Strains; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Satiation; Sincalide

Topics: Appetite; Appetite Regulation; Cholecystokinin; Digestive System Physiological Phenomena; Eating; Gastrointestinal Hormones; Humans; Hunger; Hyperphagia; Peptide Fragments; Satiation; Sincalide

Cholecystokinin (CCK) secreted from the duodenum during feeding has been shown to elicit satiety and stimulate growth of the pancreas in addition to affecting gastrointestinal function. In previous experiments hyperphagic Zucker obese rats were less sensitive to the effects of CCK on satiety and had a smaller pancreas than normal-weight rats. In the present experiments with hyperphagic lactating Zucker rats, the food intake response to exogenously administered CCK and the size and composition of the pancreas were measured. Food intakes after a 2-h fast were not decreased by 4.0 or 8.0 micrograms/kg CCK-8 during wk 1, 2, or 3 of lactation. However, in the same rats 2 wk after pups were weaned, 4.0 and 8.0 micrograms/kg CCK-8 decreased food intake 32% (2.1 +/- 0.4 vs. 3.1 +/- 0.3 g, paired t = 2.33, P less than 0.03) and 52% (1.5 +/- 0.2 vs. 3.1 +/- 0.5 g, paired t = 3.48, P less than 0.006). On day 18 of lactation, pancreas weight was increased 41% (1.38 +/- 0.05 vs. 0.98 +/- 0.02 g, paired t = 2.68, P less than 0.02) and contents of DNA, RNA, and protein were increased 57, 57, and 73%, respectively. Thus, hyperphagia in lactating female rats was associated with 1) decreased sensitivity to the satiety effect of CCK similar to that in hyperphagic obese rats and 2) hypertrophy of the pancreas in contrast to decreased pancreas size in obese rats.

Topics: Animals; Cholecystokinin; DNA; Dose-Response Relationship, Drug; Eating; Feeding and Eating Disorders; Female; Humans; Hyperphagia; Lactation; Organ Size; Pancreas; Peptide Fragments; Pregnancy; Proteins; Rats; Rats, Zucker; RNA; Sincalide