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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

Abdominal vagal mediation of the satiety effects of CCK in rats. Am J Physiol Regul Integr Comp Physiol 286: R1005-R1012, 2004. First published December 30, 2003; 10.1152/ ajpregu.00646.2003.--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 [micro]mol/kg iv) or a 3-h infusion of A-70104 (3 [micro]mol x [kg.sup.-1] x [h.sup.-1] iv) 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. receptor antagonist; devazepide; A-70104; vagotomy; satiety

Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated, in part, by CCK action at CCKARs located peripheral to the blood-brain barrier. At dark onset, non-food-deprived rats received a bolus injection of devazepide (2.5 [micro]mol/kg iv), a 3-h infusion of A-70104 (1 or 3 [micro]mol* [kg.sup.-1]*[h.sup.-1] iv), or vehicle either alone or coadministered with a 3-h infusion of CCK-8 (10 nmol*[kg.sup.-1]*[h.sup.-1] iv) or a 2-h intragastric infusion of peptone (1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N[alpha]-3-quinolinoyl-D-Glu-N,N-dipentylamide (A-65186), does not. CCK-8 inhibited 3-h food intake by more than 50% and both A-70104 and devazepide abolished this response. A-70104 and devazepide stimulated food intake and similarly attenuated the anorexic response to intragastric infusion of peptone. Thus endogenous CCK appears to act, in part, at CCKARs peripheral to the blood-brain barrier to inhibit food intake. receptor antagonist; devazepide; A-70104; satiety

Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that duodenal delivery of protein, carbohydrate, and fat produces satiety in part by an essential CCK action at CCKARs located peripheral to the blood-brain barrier. Fasted rats with open gastric fistulas received devazepide (1 mg/kg iv) or A-70104 (700 nmol*[kg.sup.-1]*[h.sup.-1] iv) and either a 30-min intravenous infusion of CCK-8 (10 nmol*[kg.sup.-1]*[h.sup.-1]) or duodenal infusion of peptone, maltose, or Intralipid beginning 10 min before 30-min access to 15% sucrose. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N[alpha]-3-quinolinoyl-D-Glu-N,N-dipentylamide, does not. CCK-8 inhibited sham feeding by ~50%, and both A-70104 and devazepide abolished this response. Duodenal infusion of each of the macronutrients dose dependently inhibited sham feeding. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Thus endogenous CCK appears to act in part at CCKARs peripheral to the blood-brain barrier to inhibit food intake. receptor antagonist; devazepide; A-70104; satiety

Type A CCK receptor (CCKAR) antagonists differing in blood-brain barrier permeability [devazepide penetrates; the dicyclohexylammonium salt of N[alpha]-3-quinolinoyl-D-Glu-N,N-dipentylamide (A-70104) does not] were used to test the hypothesis that duodenal nutrient-induced inhibition of gastric emptying is mediated by CCKARs located peripheral to the blood-brain barrier. Rats received A-70104 (700 or 3,000 nmol * [kg.sup.-1] * [h.sup.-1] iv) or devazepide (2.5 [micro]mol/kg iv) and either a 15-min intravenous infusion of CCK-8 (3 nmol * [kg.sup.-1] * [h.sup.-1) or duodenal infusion of casein, peptone, Intralipid, or maltose. Gastric emptying of saline was measured during the last 5 min of each infusion. A-70104 and devazepide abolished the gastric emptying response to a maximal inhibitory dose of CCK-8. Each of the macronutrients inhibited gastric emptying. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Intravenous injection of a CCK antibody to immunoneutralize circulating CCK had no effect on peptone or Intralipid-induced responses. Thus endogenous CCK appears to act in part by a paracrine or neurocrine mechanism at CCKARs peripheral to the blood-brain barrier to inhibit gastric emptying. receptor antagonist; devazepide; A-70104; immunoneutralization; macronutrient

We previously demonstrated that amylin inhibits food intake and gastric emptying in rats with half-maximal effective doses (E[D.sub.50]s) of 8 and 3 pmol*[kg.sup.-1]*[min.sup.-1] and maximal inhibitions of 78 and 60%, respectively. In this study of identical design, rats received intravenous infusions of salmon calcitonin (sCT), rat calcitonin (rCT), rat calcitonin gene-related peptide (rCGRP), and rat adrenomedullin (rADM) for 3 h at dark onset, and food intake was measured for 17 h or for 15 min and gastric emptying of saline was measured during the final 5 min. sCT, rCGRP, and rADM inhibited food intake with estimated E[D.sub.50]s of 0.5, 26, and 35 pmol*[kg.sup.-1]*[min.sup.-1] and maximal inhibitions of 88, 90, and 49%, respectively, rCT was not effective at doses up to 100 pmol*[kg.sup.-1]*[min.sup.-1]. sCT, rCGRP, rADM, and rCT inhibited gastric emptying with E[D.sub.50]s of 1, 130, 160, and 730 pmol*[kg.sup.-1]*[min.sup.-1] and maximal inhibitions of 60, 66, 60, and 33%, respectively. These results suggest that amylin and sCT may act by a common mechanism to decrease food intake, which includes inhibition of gastric emptying. calcitonin; calcitonin gene-related peptide; adrenomedullin; anorexia; potency

Male Wistar rats were analyzed after receiving subcutaneous infusions of islet amyloid polypeptide (IAPP) to determine the effects of amylin on food intake and feeding behavior. Subcutaneous infusions of IAPP reduced meal frequency and caused anorexia during the dark and light phases of the diurnal cycle in male. Wistar rats. Furthermore, high plasma IAPP levels reduced body weight gain due to altered feeding behavior.

Food consumption in rats is suppressed by cholecystokinin through a nonendocrine process. The cholecystokinin monoclonal antibody (CCK MAb) immuno neutralizes CCK. This property is used for testing CCK-enhanced satiety by endocrine processes. The suppression is determined from the study of the characterization of CCK MAb effects on pancreatic secretion. CCK MAb produces a dose-dependent inhibition of amylase secretion.

Reidelberger, Roger D., Urban Arnelo, Lars Granqvist, and Johan Permert. Comparative effects of amylin and cholecystokinin on food intake and gastric emptying in rats. Am J Physiol Regulatory Integrative Comp Physiol 280: R605-R611, 2001.--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.sub.50]s) of 3 and 35 pmol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1] and maximal inhibitions of 60 and 65%, respectively. Amylin and CCK-8 inhibited food intake with [ED.sub.50]s of 8 and 14 pmol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1] and maximal inhibitions of 78 and 69%, respectively. The minimal effective amylin dose for each effect was 1 pmol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-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. meal patterns; satiety; stomach; intravenous; potency; efficacy

Faro, Constance J., Roger D. Reidelberger, and Jeffrey M. Palmer. Suppression of food intake is linked to enteric inflammation in nematode-infected rats. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 278: R118-R124, 2000.--Our aim was to investigate the cause-effect relationship between intestinal inflammation induced by infection with enteric stages of Trichinella spiralis and decreased host food intake. A suppression of food intake in T. spiralis-infected rats occurred within the first 24 h postinfection (PI) and was maximized by day 6 PI. Food intake, cumulated over an 8-day PI period, decreased by 59% compared with uninfected animals. The anti-inflammatory glucocorticoid betamethasone 21-phosphate was orally administered to rats in their drinking water to suppress T. spiralis-induced jejunal inflammation. When treated with a low dose of glucocorticoid (5.2 [micro]g/ml), food intake in infected rats was still significantly reduced, but only by 21% compared with glucocorticoid-treated, uninfected rats. At the highest glucocorticoid dose (10.4 [micro]g/ml) administered, infection-induced reduction in food intake was not different from that of glucocorticoid-treated, uninfected counterparts. The elevation in jejunal myeloperoxidase activity caused by infection was also significantly blunted by oral glucocorticoid treatment. Our results suggest that suppressed host food intake during enteric T. spiralis infection is directly linked to intestinal inflammation. feeding behavior; Trichinella spiralis; betamethasone 21-phosphate; anti-inflammatory glucocorticoid; mucosal inflammation; small intestine; myeloperoxidase activity

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]

Oxidative stress from fat accumulation in the liver has many deleterious effects. Many believe that there is a second hit that causes relatively benign fat accumulation to transform into liver failure. Therefore, we evaluated the effects of ethanol on ex vivo precision-cut liver slice cultures (PCLS) from rats fed a high-fat diet resulting in fatty liver. Age-matched male Sprague-Dawley rats were fed either high-fat (obese) (45% calories from fat, 4.73 kcal/g) or control diet for 13 mo. PCLS were prepared, incubated with 25 mM ethanol for 24, 48, and 72 h, harvested, and evaluated for ethanol metabolism, triglyceride production, oxidative stress, and cytokine expression. Ethanol metabolism and acetaldehyde production decreased in PCLS from obese rats compared with age-matched controls (AMC). Increased triglyceride and smooth muscle actin production was observed in PCLS from obese rats compared with AMC, which further increased following ethanol incubation. Lipid peroxidation, measured by thiobarbituric acid reactive substances assay, increased in response to ethanol, whereas GSH and heme oxygenase I levels were decreased. TNF-α and IL-6 levels were increased in the PCLS from obese rats and increased further with ethanol incubation. Diet-induced fatty liver increases the susceptibility of the liver to toxins such as ethanol, possibly by the increased oxidative stress and cytokine production. These findings support the concept that the development of fatty liver sensitizes the liver to the effects of ethanol and leads to the start of liver failure, necrosis, and eventually cirrhosis.

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.