Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in diet-induced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dose-dependently reduces food intake and body weight to a similar extent in rats maintained on either diet. Moreover, the effect of oxytocin to induce weight loss remained intact in leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats relative to their lean littermates. To determine whether systemically administered oxytocin activates hindbrain areas that regulate meal size, we measured neuronal c-Fos induction in the nucleus of the solitary tract (NTS) and area postrema (AP). We observed a robust neuronal response to oxytocin in these hindbrain areas that was unexpectedly increased in rats rendered obese on a HFD relative to lean, LFD-fed controls. Finally, we report that repeated daily peripheral administration of oxytocin in DIO animals elicited a sustained reduction of food intake and body weight while preventing the reduction of energy expenditure characteristic of weight-reduced animals. These findings extend recent evidence suggesting that oxytocin circumvents leptin resistance and induces weight-loss in DIO animals through a mechanism involving activation of neurons in the NTS and AP, key hindbrain areas for processing satiety-related inputs.

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.

An improved methodology is described for long-term venous and gastric cannulation in the rat. The long-term efficacy of the cannulas for blood sampling and intragastric infusion of liquid diet was determined in 18 rats. No animals died after surgery, and weight gain was normal. During the first 6 wk, blood could be drawn repetitively in 94% of the rats, and continuous intragastric infusion of diet was maintained in all the animals. For an extended period of 11 wk, success rates for blood sampling and dietary infusion were 75 and 100%, respectively. Standard hematological, histopathological, and clinical laboratory tests showed no abnormal changes. Furthermore, plasma corticosterone levels were consistently low (0.5 +/- 0.11 to 1.52 +/- 0.55 micrograms/dl) from the third postoperative day throughout a period of 6 wk, indicating that animals were under minimal stress.

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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-

CCK is a physiological inhibitor of gastric emptying and food intake. The pancreatic peptide amylin exerts similar actions, yet its physiological importance is uncertain. Objectives were to compare the dose-dependent effects of intravenous infusion of amylin and CCK-8 on gastric emptying and food intake in rats, and to assess whether physiological doses of amylin are effective. Amylin and CCK-8 inhibited gastric emptying with mean effective doses (ED(50)s) of 3 and 35 pmol x kg(-1) x min(-1) and maximal inhibitions of 60 and 65%, respectively. Amylin and CCK-8 inhibited food intake with ED(50)s of 8 and 14 pmol x kg(-1) x min(-1) and maximal inhibitions of 78 and 69%, respectively. The minimal effective amylin dose for each effect was 1 pmol x kg(-1) x min(-1). Our previous work suggests that this dose increases plasma amylin by an amount comparable to that produced by a meal. These results support the hypothesis that amylin acts as a hormonal signal to the brain to inhibit gastric emptying and food intake and that amylin produces satiety in part through inhibition of gastric emptying.

CCK type 1 (CCK1) receptor antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated in part by CCK action at CCK1 receptors on vagal sensory nerves innervating the small intestine. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N alpha-3-quinolinoyl-D-Glu-N,N-dipentylamide, does not. At dark onset, non-food-deprived control rats and rats with subdiaphragmatic vagotomies received a bolus injection of devazepide (2.5 micromol/kg i.v.) or a 3-h infusion of A-70104 (3 micromol.kg(-1).h(-1) i.v.) either alone or coadministered with a 2-h intragastric infusion of peptone (0.75 or 1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. In control rats both antagonists stimulated food intake and attenuated the anorexic response to intragastric infusion of peptone. In contrast, only devazepide was effective in stimulating food intake in vagotomized rats. Thus endogenous CCK appears to act both at CCK1 receptors beyond the blood-brain barrier and by a CCK1 receptor-mediated mechanism involving abdominal vagal nerves to inhibit food intake.