Peptide YY (3-36) [PYY (3-36)] is postulated to act as a hormonal signal from the gut to the brain to inhibit food intake and gastric emptying. A mixed-nutrient meal produces a prolonged 2-3 h increase in plasma levels of both PYY (3-36) and PYY (1-36). We determined the dose-dependent effects of 3-h iv infusions of PYY (3-36) and PYY (1-36) (0.5-50 pmol.kg(-1).min(-1)) at dark onset on food intake in non-food-deprived rats. PYY (3-36) dose-dependently inhibited food intake: the minimal effective dose was 5 pmol.kg(-1).min(-1); the estimated potency (mean effective dose) and efficacy (maximal percent inhibition) were 15 pmol.kg(-1).min(-1) (2.6 nmol/kg) and 47%, respectively. PYY (1-36) was an order of magnitude less potent than PYY (3-36). Similar total doses of PYY (3-36) (0.9-30 nmol/kg) infused during the 15-min period just before dark onset also dose-dependently inhibited food intake, albeit with a lower potency and efficacy. Other experiments showed that PYY (3-36) inhibited food intake in sham-feeding rats and was more effective in reducing intake of a mixed-nutrient liquid diet than 15% aqueous sucrose. We conclude that: 1) iv infusions of PYY (3-36), which are more likely than ip injections to mimic postprandial increases in plasma PYY (3-36), potently inhibit food intake in a dose-dependent manner; 2) PYY (1-36) is an order of magnitude less potent than PYY (3-36); and 3) PYY (3-36) can inhibit food intake independently of its action to inhibit gastric emptying. It remains to be determined whether iv doses of PYY (3-36) that reproduce postprandial increases in plasma PYY (3-36) are sufficient to inhibit food intake.

Glucagon-like peptide-1(7-36)-amide (GLP-1) is postulated to act as a hormonal signal from gut to brain to inhibit food intake and gastric emptying. A mixed-nutrient meal produces a 2 to 3-h increase in plasma GLP-1. We determined the effects of intravenous infusions of GLP-1 on food intake, sham feeding, and gastric emptying in rats to assess whether GLP-1 inhibits food intake, in part, by slowing gastric emptying. A 3-h intravenous infusion of GLP-1 (0.5-170 pmol.kg(-1).min(-1)) at dark onset dose-dependently inhibited food intake in rats that were normally fed with a potency (mean effective dose) and efficacy (maximal % inhibition) of 23 pmol.kg(-1).min(-1) and 82%, respectively. Similar total doses of GLP-1 administered over a 15-min period were less potent and effective. In gastric emptying experiments, GLP-1 (1.7-50 pmol.kg(-1).min(-1)) dose-dependently inhibited gastric emptying of saline and ingested chow with potencies of 18 and 6 pmol.kg(-1).min(-1) and maximal inhibitions of 74 and 83%, respectively. In sham-feeding experiments, GLP-1 (5-50 pmol.kg(-1).min(-1)) dose-dependently reduced 15% aqueous sucrose intake in a similar manner when gastric cannulas were closed (real feeding) and open (sham feeding). These results demonstrate that intravenous infusions of GLP-1 dose-dependently inhibit food intake, sham feeding, and gastric emptying with a similar potency and efficacy. Thus GLP-1 may inhibit food intake in part by reducing gastric emptying, yet can also inhibit food intake independently of its action to reduce gastric emptying. It remains to be determined whether intravenous doses of GLP-1 that reproduce postprandial increases in plasma GLP-1 are sufficient to inhibit food intake and gastric emptying.

reduces food intake and weight gain in rats when injected into the peritoneal cavity twice daily for 7 days. Numerous laboratories have failed to confirm that daily injections of PYY(3-36) decrease body weight. Continuous subcutaneous administration of PYY(3-36) by osmotic minipump has been reported to reduce daily food intake in rodents but only during the first 3-4 days of administration. Here we show the effects of different daily patterns of intravenous infusion of PYY(3-36) on food intake, body weight, and adiposity in rats tethered via infusion swivels to computercontrolled pumps. Measurement of food bowl weight recorded by computer every 20 s permitted daily assessment of the instantaneous effects of PYY(3-36) administration on food intake and meal patterns. One-hour intravenous infusions of PYY(3-36) at 30 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 every other hour for 10 days produced a sustained reduction in daily food intake of ϳ20% and decreased body weight and adiposity by 7 and 35%, respectively. Thus dosage pattern is critical for producing a sustained effect of PYY(3-36) on food intake and adiposity.gastrointestinal; body weight; body composition THE GASTROINTESTINAL SYSTEM plays an important sensing and signaling role in control of food intake and regulation of energy reserves (5). A growing number of peptide signals of gastric, intestinal, and pancreatic origin have been shown to inhibit short-term food intake when administered acutely to experimental animals and humans. These include cholecystokinin, amylin, glucagon-like peptide-1 (GLP-1), oxyntomodulin, peptide YY(3-36) ], pancreatic polypeptide, gastrinreleasing peptides (GRPs) GRP-27 and GRP-

Amylin is postulated to act as a hormonal signal from the pancreas to the brain to inhibit food intake and regulate energy reserves. Amylin potently reduces food intake, body weight, and adiposity when administered systemically or into the brain. Whether selective blockade of endogenous amylin action increases food intake and adiposity remains to be clearly established. In the present study, the amylin receptor antagonist acetyl-[Asn(30), Tyr(32)] sCT-(8-32) (AC187) was used to assess whether action of endogenous amylin is essential for normal satiation to occur. Non-food-deprived rats received a 3- to 4-h intravenous infusion of AC187 (60-2,000 pmol.kg(-1).min(-1)), either alone or coadministered with a 3-h intravenous infusion of amylin (2.5 or 5 pmol.kg(-1).min(-1)) or a 2-h intragastric infusion of an elemental liquid diet (4 kcal/h). Infusions began just before dark onset. Food intake and meal patterns during the first 4 h of the dark period were determined from continuous computer recordings of changes in food bowl weight. Amylin inhibited food intake by approximately 50%, and AC187 attenuated this response by approximately 50%. AC187 dose-dependently stimulated food intake (maximal increases from 76 to 171%), whether administered alone or with an intragastric infusion of liquid diet. Amylin reduced mean meal size and meal frequency, AC187 attenuated these responses, and AC187 administration alone increased mean meal size and meal frequency. These results support the hypothesis that endogenous amylin plays an essential role in reducing meal size and increasing the postmeal interval of satiety.

Malondialdehyde and acetaldehyde react together with proteins and form hybrid protein conjugates designated as MAA adducts, which have been detected in livers of ethanol-fed animals. Our previous studies have shown that MAA adducts are comprised of two distinct products. One adduct is composed of two molecules of malondialdehyde and one molecule of acetaldehyde and was identified as the 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde derivative of an amino group (MDHDC adduct). The other adduct is a 1:1 adduct of malondialdehyde and acetaldehyde and was identified as the 2-formyl-3-(alkylamino)butanal derivative of an amino group (FAAB adduct). In this study, information on the mechanism of MAA adduct formation was obtained, focusing on whether the FAAB adduct serves as a precursor for the MDHDC adduct. Upon the basis of chemical analysis and NMR spectroscopy, two initial reaction steps appear to be a prerequisite for MDHDC formation. One step involves the reaction of one molecule of malondialdehyde and one of acetaldehyde with an amino group of a protein to form the FAAB product, while the other step involves the generation of a malondialdehyde-enamine. It appears that generation of the MDHDC adduct requires the FAAB moiety to be transferred to the nitrogen of the MDA-enamine. For efficient reaction of FAAB with the enamine to take place, additional experiments indicated that these two intermediates likely must be in positions on the protein of close proximity to each other. Further studies showed that the incubation of liver proteins from ethanol-fed rats with MDA resulted in a marked generation of MDHDC adducts, indicating the presence of a pool of FAAB adducts in the liver of ethanol-fed animals. Overall, these findings show that MDHDC-protein adduct formation occurs via the reaction of the FAAB moiety with a malondialdehyde-enamine, and further suggest that a similar mechanism may be operative in vivo in the liver during prolonged ethanol consumption.

We compared the effects of the two molecular forms of the brain-gut peptide YY (PYY), PYY(1-36) and PYY(3-36), on gastric emptying. Unanesthetized rats received 20-min intravenous infusions of rat PYY(1-36) (0, 1.7, 5, 17, 50, 100, 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and rat PYY(3-36) (0, 0.5, 1.7, 5, 17, 50, 100, 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ), either alone or combined, and gastric emptying of saline was measured during the last 10 min of infusion. For comparison, human PYY(3-36) was administered at 0, 17, and 50 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 . Gastric emptying was decreased by 11, 24, 26 and 38% in response to 17, 50, 100, and 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 of rat PYY(1-36); by 10, 26, 41, 53, and 57% in response to 5, 17, 50, 100, and 170 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 of rat PYY(3-36); and by 35 and 53% in response to 17 and 50 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 of human PYY(3-36), respectively. Estimated ED50s were 470 and 37 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 for rat PYY(1-36) and PYY(3-36), respectively. In general, within an experiment, coadministration of PYY(1-36) and PYY(3-36) inhibited gastric emptying by an amount that was comparable to that produced when either peptide was given alone. We conclude that 1) intravenous infusion of PYY(1-36) and PYY(3-36) each produces a dose-dependent inhibition of gastric emptying in rats, 2) PYY(3-36) is an order of magnitude more potent than PYY(1-36) in inhibiting gastric emptying, 3) human PYY(3-36) and rat PYY(3-36) inhibit gastric emptying similarly, and 4) PYY(1-36) and PYY(3-36) do not appear to interact in an additive or synergistic manner to inhibit gastric emptying. intravenous infusion; dose response; interaction PEPTIDE YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP) comprise the "PP-fold" family of structurally related brain-gut peptides. PYY is synthesized in the gastrointestinal tract, as well as in the central and peripheral nervous systems. Endocrine cells of the ileum, colon, and rectum provide a major source of PYY (2, 47). PYY has also been detected in gastric mucosa, pancreatic islets, myenteric and serosal ganglia, sympathetic neurons, adrenal gland, spinal cord, and brain, including the hypothalamus, pituitary, pons, medulla oblongata, and the brain stem (7-9, 15, 16, 22, 30, 32, 37).Food intake releases PYY into the circulation (2, 47). Systemic administration of PYY inhibits food intake, gastric emptying, intestinal fluid and electrolyte secretion, gallbladder contraction, and exocrine pancreatic secretion (5, 36). Whether PYY acts physiologically by endocrine, neurocrine, and/or paracrine mechanisms to produce these effects remains to be determined. If PYY acts as a blood-borne hormonal signal to produce an effect, then it is important to determine whether the effect is produced by intravenous doses of PYY that reproduce meal-induced increases in plasma PYY.The two major molecular forms of PYY found in the gut and circulation are PYY(1-36) and PYY(3-36) (19 -21). In humans, plasma concentrations of PYY were reported to be 11 pM in the fasted state with PYY(3-36) contributing 37% ...

Ghrelin stimulates, while glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) [PYY(3-36)] inhibit, food intake and gastric emptying in rats. We determined the dose-dependent effects of a 3-h intravenous infusion of ghrelin at dark onset on food intake in freely feeding rats, and on the inhibitory effects of intravenous infusion of GLP-1 and PYY(3-36) on food intake and gastric emptying. Ghrelin (150 pmol ⅐ kg ؊1 ⅐ min ؊1 ) stimulated food intake by 28% during the infusion period primarily by increasing meal frequency; doses of 15 and 50 pmol ⅐ kg ؊1 ⅐ min ؊1 had no effect. GLP-1 (15 pmol ⅐ kg ؊1 ⅐ min ؊1 ) inhibited food intake by 35-54%; coinfusion of ghrelin at 50 and 150 pmol ⅐ kg These results suggest that ghrelin may stimulate food intake in part by attenuating the inhibitory effects of GLP-1 and PYY(3-36) on gastric emptying and food intake.

Chelikani PK, Haver AC, Reidelberger RD. Intermittent intraperitoneal infusion of peptide YY(3-36) reduces daily food intake and adiposity in obese rats. Am J Physiol Regul Integr Comp Physiol 293: R39-R46, 2007. First published April 11, 2007; doi:10.1152/ajpregu.00164.2007 ] is a gut-brain peptide that decreases food intake when administered by intravenous infusion to lean and obese humans and rats. However, chronic administration of PYY(3-36) by osmotic minipump to lean and obese rodents produces only a transient reduction in daily food intake and weight gain. It has recently been shown that 1-h intravenous infusions of PYY(3-36) every other hour for 10 days produced a sustained reduction in daily food intake, body weight, and adiposity in lean rats. Here, we determined whether intermittent delivery of PYY(3-36) can produce a similar response in diet-induced obese rats. During a 21-day period, obese rats (body fat Ͼ25%) received twice daily intraperitoneal infusion of vehicle (n ϭ 18) or PYY(3-36) (n ϭ 24) during hours 1-3 and 7-9 of the dark period. Rats had free access to both a 45% fat solid diet and a 29% fat liquid diet; intakes were determined from continuous computer recording of changes in food container weights. To sustain a 15-25% reduction in daily caloric intake, the initial PYY(3-36) dose of 30 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 was reduced to 10 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 on day 10 and then increased to 17 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 on day 13. This dosing strategy produced a sustained reduction in daily caloric intake of 11-32% and prevented body weight gain (8 Ϯ 6 vs. 51 Ϯ 11 g) and fat deposition (4.4 Ϯ 7.6 vs. 41.0 Ϯ 12.8 g). These results indicate that intermittent intraperitoneal infusion of PYY(3-36) can produce a sustained reduction in food intake and adiposity in diet-induced obese rodents consuming palatable high-fat foods.peptide; anorexia; body weight; body fat PEPTIDE YY (PYY), neuropeptide Y, and pancreatic polypeptide comprise a family of structurally related gut-brain peptides with diverse actions mediated by five known receptors (12). Endocrine cells of the distal gut provide a major source of PYY. Food intake releases at least two major forms of PYY into the circulation: PYY(1-36) and PYY(3-36); other predicted or detected isoforms include Ser 13 -phosphorylated PYY(1-36) and PYY(3-36), glycine-extended carboxyl termini of both the phosphorylated and nonphosphorylated forms, and [Pro 34 ]PYY(3-36) (4,17,21,24). Systemic administration of PYY(3-36) potently inhibits food intake in rodents, monkeys, and humans (11,15,19,27,28,33,40), whereas PYY(1-36) appears to be significantly less potent in rats (15) and humans (39). Targeted deletion of the PYY gene produces an obese phenotype in mice (13). Obese humans appear to have a blunted plasma PYY response to food intake (10, 28); however, PYY(3-36) appears to decrease food intake similarly in lean and obese humans (10, 39). These results suggest that PYY(3-36) may act physiologically to reduce food intake and body adiposity and that insufficient produc...