sincalide and Weight-Loss

The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7-36) (GLP-1 (7-36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP-1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24-h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action.

Topics: Animals; Anti-Obesity Agents; Aorta; Cholecystokinin; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Eating; Feeding Behavior; Glucagon-Like Peptide 1; Male; Obesity; Peptide Fragments; Rats, Sprague-Dawley; Satiation; Time Factors; Weight Loss

We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW.

Topics: Animals; Body Weight; Cholecystokinin; Diet; Drug Therapy, Combination; Gastrin-Releasing Peptide; Gastrointestinal Agents; Infusions, Parenteral; Male; Obesity; Peptide Fragments; Rats; Weight Loss

CCK octapeptide (CCK-8) is released by the gut in response to a meal and acts via CCK(A) receptors on vagal afferents to induce satiety. However, the central neural pathways by which peripheral CCK-8 affects feeding are poorly understood. In the present study, we tested the hypothesis that norepinephrine (NE) is necessary for satiety induced by peripheral CCK-8 by using mice lacking dopamine beta-hydroxylase (Dbh(-/-)), the enzyme responsible for synthesizing NE and epinephrine from dopamine. We found that Dbh(-/-) mice are as responsive to the satiating effects of CCK-8 as their normal littermates.

Topics: Animals; Cholecystokinin; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Feeding Behavior; Female; Food Deprivation; Gene Deletion; Male; Mice; Mice, Knockout; Norepinephrine; Peptide Fragments; Satiety Response; Weight Gain; Weight Loss

The Koletsky ("corpulent) obese rat is homozygous for an autosomal recessive mutation of the leptin receptor (Lepr) that results in hyperphagia, obesity, and hyperlipidemia. Unlike the Lepr mutation that characterizes the fatty Zucker rat (Lepr(fa)), the Koletsky mutation (Lepr(fak)) is null. Because the Lepr(fak) mutation is null, exogenous leptin should have no effect on body weight or food intake in fa(k)/fa(k) rats. We confirmed that prediction: murine leptin, administered into the third ventricle for 5 consecutive days, did not affect daily food intake or body weight in fa(k)/fa(k) rats but produced dose-related inhibitions of food intake and body weight in +/+ and +/fa(k) rats. Although fa(k)/fa(k) rats did not respond to leptin, their response to CCK-8 (4 microg/kg ip) injected before 30-min test meals of 10% sucrose was not different from that of +/+ or +/fa(k) rats. These results demonstrate that the fa(k)/fa(k) rat is a good model in which to analyze the controls of food intake, energy expenditure, and energy storage in the absence of leptin effects.

Topics: Animals; Carrier Proteins; Dietary Sucrose; Disease Models, Animal; Eating; Injections, Intraventricular; Leptin; Obesity; Rats; Rats, Mutant Strains; Receptors, Cell Surface; Receptors, Leptin; Satiation; Sincalide; Weight Gain; Weight Loss

Wheat amylase inhibitor (WAI) was given to growing rats to determine whether chronic inhibition of intraluminal amylase activity alters pancreatic growth, pancreatic enzyme composition, and secretory responsiveness to cholecystokinin octapeptide (CCK-OP) and carbachol. For 21 days 13 rats were fed amylase inhibitor (AI) as 2.72% of the weight of their food; 13 were pair-fed controls (PFC), and 12 were controls with free access to food (FAC). Amylase and lipase secretion was measured from isolated pancreatic acini in response to CCK-OP (10(-12)-10(-8) M) and carbachol (10(-8)-10(-3) M). AI and PFC rats had similar food intakes and weight gains, pancreatic weights, and contents of enzymes (amylase, lipase, trypsin, chymotrypsin), protein, and RNA, but these measurements were significantly reduced compared to those of FAC rats. DNA contents per milligram of pancreas and per gram of body weight and amylase/DNA and trypsin/DNA were similar among all groups. Lipase/DNA and chymotrypsin/DNA in AI rats were the same as in PFC rats but significantly lower than in FAC rats. In response to CCK-OP, amylase secretion was similar in all three groups, but in response to carbachol amylase secretion was significantly less in AI compared to PFC and FAC rats. Lipase secretion increased in response to CCK-OP in AI compared to PFC and FAC rats but was similar in all three groups in response to carbachol. Long-term inhibition of intraluminal amylase activity suppresses pancreatic growth and content of enzymes and RNA by reducing food intake and weight gain and also decreases acinar cell secretion of amylase in response to carbachol and increases lipase secretion in response to CCK-OP.

Topics: Amylases; Animals; Carbachol; DNA; Eating; Enzyme Inhibitors; Lipase; Male; Muscarinic Agonists; Pancreas; Plant Proteins; Rats; Rats, Wistar; RNA; Sincalide; Weight Loss