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Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces either no effect or a transient reduction in food intake and body weight. Our aim here was to identify an intermittent dosing strategy for intraperitoneal infusion of peptide YY(3-36) [PYY(3-36)] that produces a sustained reduction in daily food intake and adiposity in diet-induced obese rats. Rats (665 [+ or -] 10 g body wt, 166 [+ or -] 7 g body fat) with intraperitoneal catheters tethered to infusion swivels had free access to a high-fat diet. Vehicle-treated rats (n = 23) had relatively stable food intake, body weight, and adiposity during the 9-wk test period. None of 15 PYY(3-36) dosing regimens administered in succession to a second group of rats (n = 22) produced a sustained 15-25% reduction in daily food intake for >5 days, although body weight and adiposity were reduced across the 9-wk period by 12% (594 [+ or -] 15 vs. 672 [+ or -] 15 g) and 43% (96 [+ or -] 7 vs. 169 [+ or -] 9 g), respectively. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was [greater than or equal to] 3 h appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was < 3 h suggested possible receptor downregulation and tolerance to frequent PYY(3-36) administration; however, food intake significantly increased when PYY(3-36) treatments were discontinued for 1 day following apparent loss in treatment efficacies. Together, these results demonstrate the development of a potent homeostatic response to increase food intake when PYY(3-36) reduces food intake and energy reserves in diet-induced obese rats. gastrointestinal; peptide; intraperitoneal administration; anorexia; body composition

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces no effect or a transient reduction in daily food intake and body weight. Our aim was to identify an intermittent dosing strategy for intraperitoneal infusion of salmon calcitonin (sCT), a homolog of amylin that produces a sustained 25-35% reduction in daily food intake and adiposity in diet-induced obese rats. Rats (649 [+ or -] 10 g body wt, 27 [+ or -] 1% body fat), with intraperitoneal catheters tethered to infusion swivels, had free access to a 45% fat diet. Food intake, body weight, and adiposity during the 7-wk test period were relatively stable in the vehicle-treated rats (n = 16). None of 10 sCT dosing regimens administered in succession to a second group of rats (n = 18) produced a sustained 25-35% reduction in daily food intake for >5 days, although body weight and adiposity were reduced by 9% (587 [+ or -] 12 vs. 651 [+ or -] 14 g) and 22% (20.6 [+ or -] 1.2 vs. 26.5 [+ or -] 1.1%), respectively, across the 7-wk period. The declining inhibitory effect of sCT on daily food intake with the 6-h interinfusion interval appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of sCT on daily food intake with the 2- to 3-h interinfusion interval suggested possible receptor downregulation and tolerance to frequent sCT administration; however, food intake increased dramatically when sCT was discontinued for 1 day after apparent loss of treatment efficacy. Together, these results demonstrate the activation of a potent homeostatic response to increase food intake when sCT reduces food intake and energy reserves in diet-induced obese rats. amylin; anorexia; body weight; body fat

Peptide YY(3-36) [PYY(3-36)] 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 >25%) received twice daily intraperitoneal infusion of vehicle (n = 18) or PYY(3-36) (n = 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 x [kg.sup.-1] x [min.sup.-1] was reduced to 10 pmol x [kg.sup.-1] x [min.sup.-1] on day 10 and then increased to 17 pmol x [kg.sup.-l] x [min.sup.-1] on day 13. This dosing strategy produced a sustained reduction in daily caloric intake of 11-32% and prevented body weight gain (8 [+ or -] 6 vs. 51 [+ or -] 11 g) and fat deposition (4.4 [+ or -] 7.6 vs. 41.0 [+ or -] 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 doi:10.1152/ajpregu.00164.2007

The gut hormone peptide YY(3-36) [PYY(3-36)] decreases food intake when administered by intravenous infusion to lean and obese humans and rats. Whether chronic administration of PYY(3-36) produces a sustained reduction in food intake and adiposity is the subject of intense debate. Batterham et al. (R. L. Batterham, M. A. Cowley, C. J. Small, H. Herzog, M. A. Cohen, C. L. Dakin, A. M. Wren, A. E. Brynes, M. J. Low, M. A. Ghatei, R. D. Cone, and S. R. Bloom. Nature 418: 650-654, 2002) first reported that PYY(3-36) 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 computer-controlled 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*[kg.sup.-1]*[min.sup.-1] every other hour for 10 days produced a sustained reduction in daily food intake of ~20% 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

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.sup.-1]*[min.sup.-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.sup.-1]*[min.sup.-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.sup.-1]*[min.sup.-1]) dose-dependently inhibited gastric emptying of saline and ingested chow with potencies of 18 and 6 pmol*[kg.sup.-1]*[min.sup.-1] and maximal inhibitions of 74 and 83%, respectively. In sham-feeding experiments, GLP-1 (5 50 pmol*[kg.sup.-1]*[min.sup.-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. satiety; dose-response; meal size; meal frequency

Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats. Am J Physiol Regul Integr Comp Physiol 287: R1064-R1070, 2004. First published July 8, 2004; doi:10.1152/ajpregu.00376.2004.--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*[kg.sup.-1]*[min.sup.-1]) and rat PYY(3-36) (0, 0.5, 1.7, 5, 17, 50, 100, 170 pmol*[kg.sup.-1]*[min.sup.-1]), 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*[kg.sup.-1]*[min.sup.-1]. Gastric emptying was decreased by 11, 24, 26 and 38% in response to 17, 50, 100, and 170 pmol*[kg.sup.-1]*[min.sup.-1] of rat PYY(1-36); by 10, 26, 41, 53, and 57% in response to 5, 17, 50, 100, and 170 pmol*[kg.sub.-1]*[min.sup.-1] of rat PYY(3-36); and by 35 and 53% in response to 17 and 50 pmol*[kg.sup.-1]*[min.sup.-1] of human PYY(3-36), respectively. Estimated [ED.sub.50]S were 470 and 37 pmol*[kg.sup.-1]*[min.sup.-1] 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

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 he clearly established. In the present study, the amylin receptor antagonist acetyl-[[Asn.sup.30], [Tyr.sup.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 x [kg.sup.-1] x [min.sup.-1]), either alone or coadministered with a 3-h intravenous infusion of amylin (2.5 or 5 pmol x [kg.sup.-1] x [min.sup.-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 ~50%, and AC187 attenuated this response by ~50%. AC 187 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. receptor antagonist; AC187; satiety; islet amyloid polypeptide

Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY3-36). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY3-36 that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY3-36 produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY3-36 on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY3-36 does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY3-36 on food intake and body weight. [ABSTRACT FROM AUTHOR]

We compared the effects of the two molecular forms of the brain-gut peptide YY (PYY), PYY(136) 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 · kg-1 · min-1 ) and rat PYY(3- 36) (0, 0.5, 1.7, 5, 17, 50, 100, 170 pmol·kg-1·min-1, 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·kg-1·min-1. Gastric emptying was decreased by 11, 24, 26 and 38% in response to 17, 50, 100, and 170 pmol·kg-l·min-1 of rat PYY(1-36); by 10, 26, 41, 53, and 57% in response to 5, 17, 50, 100, and 170 pmol·kg-1·min-1 of rat PYY(3-36); and by 35 and 53% in response to 17 and 50 pmol·kg-1·min-1 of human PYY(3-36), respectively. Estimated ED50s were 470 and 37 pmol · kg-1 · min-1 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. [ABSTRACT FROM AUTHOR]