The effect of pre-resection obesity on post-resection body composition after 75% small bowel resection in rats.

In patients with short bowel syndrome, an elevated pre-resection Body Mass Index may be protective of post-resection body composition. We hypothesized that rats with diet-induced obesity would lose less lean body mass after undergoing massive small bowel resection compared to non-obese rats. Rats (CD IGS; age = 2 mo; N = 80) were randomly assigned to either a high-fat (obese rats) or a low-fat diet (non-obese rats), and fed ad lib for six months. Each diet group then was randomized to either underwent a 75% distal small bowel resection (massive resection) or small bowel transection with re-anastomosis (sham resection). All rats then were fed ad lib with an intermediate-fat diet (25% of total calories) for two months. Body weight and quantitative magnetic resonance-determined body composition were monitored. Preoperative body weight was 884 ± 95 versus 741 ± 75 g, and preoperative percent body fat was 35.8 ± 3.9 versus 24.9 ± 4.6%; high-fat vs. low fat diet, respectively (p < 0.0001); preoperative diet type had no effect on lean mass. Regarding total body weight, massive resection produced an 18% versus 5% decrease in high-fat versus low-fat rats respectively, while sham resection produced a 2% decrease vs. a 7% increase, respectively (p < 0.0001, preoperative vs. necropsy data). Sham resection had no effect on lean mass; after massive resection, both high-fat and low-fat rats lost lean mass, but these changes were not different between the latter two rat groups. The high-fat diet and low-fat diet induced obesity and marginal obesity, respectively. The massive resection produced greater weight loss in high-fat rats compared to low-fat rats. The type of dietary preconditioning had no effect on lean mass loss after massive resection. A protective effect of pre-existing obesity on lean mass after massive intestinal resection was not demonstrated.

Inulin fiber dose-dependently modulates energy balance, glucose tolerance, gut microbiota, hormones and diet preference in high-fat-fed male rats.

Inulin, a popular prebiotic fiber, has been reported to promote satiety and fat loss; however, the dose-response effects of inulin on energy balance and diet preference, and whether the metabolic effects are independent of calorie restriction are not well characterized. Therefore, we compared the effects of diets varying in inulin concentrations on food intake, energy expenditure, body composition, gut microbiota and hormones, and assessed whether inulin-induced hypophagia was due to reduced diet preference. In experiment 1, male rats were randomized to six high-fat diet groups: control (CON, 0% inulin), 2.5% inulin (2.5IN), 10% inulin (10IN), 25% inulin (25IN), 25% cellulose (25CE) or pair-fed to 25IN (25PF) for 21 days. We demonstrate that inulin dose-dependently decreased caloric intake and respiratory quotient; improved glucose tolerance; increased the abundance of Bacteroidetes and Bifidobacterium spp.; decreased Clostridium clusters I and IV; increased butyryl-CoA:acetate CoA-transferase in cecum; upregulated peptide YY, cholecystokinin and proglucagon transcripts in the cecum and colon; and increased plasma peptide YY and glucagon-like peptide-1 concentrations. Importantly, unlike 25PF, 25IN attenuated the reduction in energy expenditure associated with calorie restriction and decreased adiposity. In experiment 2, following four training periods, diet preferences were determined. Although 10IN and 25IN decreased caloric intake, and 25CE increased caloric intake, during training, all high-fiber diets were less preferred. Taken together, this work demonstrates that inulin dose-dependently decreased caloric intake, modulated gut microbiota and upregulated satiety hormones, with metabolic effects being largely independent of caloric restriction.

Effects of solid-phase extraction of plasma in measuring gut metabolic hormones in fasted and fed blood of lean and diet-induced obese rats.

Glucagon-like peptide-1 (GLP-1), peptide YY (3-36) [PYY(3-36)], amylin, ghrelin, insulin, and leptin are thought to act as hormonal signals from periphery to brain to control food intake. Here, we determined the effects of solid-phase extraction of plasma in measuring these hormones in blood of lean and diet-induced obese rats. Individual enzyme-linked immunoassays and a multiplex assay were used to measure active GLP-1, total PYY, active amylin, active ghrelin, insulin, leptin, and total GIP in response to (1) addition of known amounts of the peptides to lean and obese plasma, (2) a large meal in lean and obese rats, and (3) intravenous infusions of anorexigenic doses of GLP-1, PYY(3-36), amylin, and leptin in lean rats. Extraction of lean and obese plasma prior to assays produced consistent recoveries across assays for GLP-1, PYY, amylin, ghrelin, and insulin, reflecting losses inherent to the extraction procedure. Plasma extraction prior to assays generally revealed larger meal-induced changes in plasma GLP-1, PYY, amylin, ghrelin, and insulin in lean and obese rats. Plasma extraction and the multiplex assay were used to compare plasma levels of GLP-1, PYY, and amylin after a large meal with plasma levels produced by IV infusions of anorexigenic doses of GLP-1, PYY(3-36), and amylin. Infusions produced dose-dependent increases in plasma peptide levels, which were well above their postprandial levels. These results do not support the hypothesis that postprandial plasma levels of GLP-1, PYY(3-36), and amylin are sufficient to decrease food intake by an endocrine mechanism.

Effect of proximal versus distal 50% enterectomy on nutritional parameters in rats preconditioned with a high-fat diet or regular chow.

Obesity may protect against the nutritional consequences of short bowel syndrome. We hypothesized that rats preconditioned with an obesogenic diet would have better outcomes after surgical induction of short bowel syndrome compared to rats on regular chow. Rats were fed a high-fat diet or regular rat chow for six months, and then underwent 50% proximal, 50% distal, or sham enterectomy. Food intake, weight, and body composition were monitored before and for 4 weeks after surgery. The high-fat diet consistently produced obesity (>25% body fat). All procedures induced weight loss, but there was no discernable difference between resection vs. sham resection. Rats on the high-fat diet had a greater post-resection loss of body fat compared to rats on chow (36 vs. 26 g, respectively). There was a nonsignificant trend of less lean mass loss in the former compared to the latter rats (16 vs. 33 g, respectively). Enterectomy moderated serum ghrelin, GIP, PPY, insulin, and leptin. Intestinal adaptation was not different between obese vs. non-obese rats. Rats preconditioned with the high-fat diet may have had better retention of lean body mass after a surgical procedure compared to rats on chow. The effect of 50% enterectomy was less than expected.

Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

Precision-cut liver slices from diet-induced obese rats exposed to ethanol are susceptible to oxidative stress and increased fatty acid synthesis.

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.

Role of peptide YY(3-36) in the satiety produced by gastric delivery of macronutrients in rats.

Peptide YY(3-36) [PYY(3-36)] is postulated to act as a hormonal signal from gut to brain to inhibit food intake. PYY(3-36) potently reduces food intake when administered systemically or into the brain. If action of endogenous PYY(3-36) is necessary for normal satiation to occur, then pharmacological blockade of its receptors should increase food intake. Here, we determined the effects of iv infusion of Y1, Y2, and Y5 receptor antagonists (BIBP 3226, BIIE 0246, CGP 71683) during the first 3 h of the dark period on food intake in non-food-deprived rats. Our results showed that 1) Y2 receptor blockade reversed the anorexic response to iv infusion of PYY(3-36) but did not increase food intake when administered alone; 2) Y1 and Y5 receptor antagonists neither attenuated PYY(3-36)-induced anorexia nor altered food intake when given alone; and 3) Y2 receptor blockade attenuated anorexic responses to gastric infusions of casein hydrolysate and long-chain triglycerides, but not maltodextrin. Previous work showed that Y2 antagonist BIIE 0246 does not penetrate the blood-brain barrier. Together, these results support the hypothesis that gut PYY(3-36) action at Y2 receptors peripheral to the blood brain barrier plays an essential role in mediating satiety responses to gastric delivery of protein and long-chain triglycerides, but not polysaccharide.

Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats.

Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg(-1)·h(-1))] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg(-1)·h(-1)) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats.

Food intake and meal pattern in IAPP knockout mice with and without infusion of exogenous IAPP.

OBJECTIVE: The current study used islet amyloid polypeptide (IAPP) knockout mice (KO mice) to investigate the physiological role of IAPP in the regulation of food intake (FI). MATERIAL AND METHODS: FI and body weight were measured in KO and wild-type (WT) mice for 27 weeks. In an additional short-term experiment, IAPP (25 pmol·kg(-1)min(-1)) was infused subcutaneously for 3 days in KO and WT mice, and FI, meal pattern, and body weight were analyzed. RESULTS: In the long-term experiment, no significant differences in body weight were seen between WT and KO mice at any point. FI, meal number, and meal size did not differ significantly between the groups in any of the five selected weeks that were studied. In the short-term experiment, FI decreased significantly during IAPP infusion in both WT and KO groups. FI was significantly lower in the KO mice compared with WT on days 1 and 2 (p < 0.05 and p < 0.01, respectively). CONCLUSIONS: The data showing no differences in FI and body weight were seen between KO and WT mice, indicating that FI can be controlled in the absence of IAPP. The more marked anorectic effect seen in the KO mice during IAPP infusion suggests that IAPP receptors and/or IAPP post-receptor signaling pathways are up-regulated in mice lacking endogenous IAPP.

Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats.

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.

Effects of glycine-extended and serine13-phosphorylated forms of peptide YY on food intake in rats.

The gut hormone peptide YY(3-36)-amide [PYY(3-36)-NH(2)] is significantly more potent than PYY(1-36)-NH(2) in reducing food intake in rats and humans. Other Gly-extended and Ser(13)-phosphorylated PYY forms have been detected or predicted based upon known cellular processes of PYY synthesis and modification. Here we compared the effects of 3-h IV infusion of PYY(1-36)-NH(2), PYY(3-36)-NH(2), PYY(1-36)-Gly-OH, PYY(3-36)-Gly-OH, Ser(13)(PO(3))-PYY(1-36)-NH(2), Ser(13)(PO(3))-PYY(3-36)-NH(2), Ser(13)(PO(3))-PYY(1-36)-Gly-OH, and Ser(13)(PO(3))-PYY(3-36)-Gly-OH during the early dark period on food intake in freely feeding rats. PYY(3-36)-NH(2) and Ser(13)(PO(3))-PYY(3-36)-NH(2) reduced food intake similarly at 50 pmol/kg/min, while only PYY(3-36)-NH(2) reduced food intake at 15 pmol/kg/min. PYY(1-36)-NH(2) and Ser(13)(PO(3))-PYY(1-36)-NH(2) reduced food intake similarly at 50 and 150 pmol/kg/min. In contrast, PYY(1-36)-Gly-OH, PYY(3-36)-Gly-OH, Ser(13)(PO(3))-PYY(3-36)-Gly-OH, and Ser(13)(PO(3))-PYY(1-36)-Gly-OH had no effect on food intake at doses of 50 or 150 pmol/kg/min. Taken together, these results indicate that (i) PYY(3-36)-NH(2) is significantly more potent than PYY(1-36)-NH(2) in reducing food intake, (ii) Gly-extended forms of PYY are significantly less potent than non-extended forms, and (iii) Ser(13)-phosphorylation of PYY(3-36)-NH(2) decreases the anorexigenic potency PYY(3-36)-NH(2), but not PYY(1-36)-NH(2). Thus, PYY(3-36)-NH(2) appears to be the most potent PYY form for reducing food intake in rats.

Effects of exendin-4 alone and with peptide YY(3-36) on food intake and body weight in diet-induced obese rats.

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 YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) 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 PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) 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 PYY(3-36) 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 PYY(3-36) on food intake and body weight.

PYY(1-36) is the major form of PYY in rat distal small intestine: quantification using high-resolution mass spectrometry.

We measured molecular forms of PYY in the distal half of rat small intestine using a new method for tissue extraction, three sequential reverse phase chromatography steps, and PYY radioimmunoassay and mass spectrometry to measure their levels. The extraction method called RAPID, developed to minimize artifactual degradation of PYY during tissue extraction and sample preparation, uses Reduced temperature, Acidified buffer, Peptidase inhibitors, Isotopically enriched mass spectrometry standards, and Dilution to inhibit and monitor endogenous peptide degradation during tissue processing. Synthetic peptides [PYY(1-36)-NH(2), PYY(3-36)-NH(2), PYY(1-36)-Gly-OH, and PYY(3-36)-Gly-OH] selectively enriched with (13)C(3)-alanine were added as internal standards to the extraction buffer. By collecting mass spectra rather than multiple-reaction-monitoring (MRM) profiles, we simultaneously screen for any PYY forms that were present in the immunoreactive fractions. PYY(1-36)-NH(2), PYY(3-36)-NH(2), PYY(1-36)-Gly-OH, and PYY(3-36)-Gly-OH were identified and quantified at 64.3±4.5, 6.1±0.9, 0.9±0.1, and <0.3pmol/g of tissue, respectively (n=3). Thus, we found that in rat distal small intestine proPYY is processed to PYY(1-36)-NH(2) with little conversion to PYY(3-36)-NH(2). These data suggest that production of PYY(3-36)-NH(2) (a form with greater potency than PYY(1-36)-NH(2) for inhibition of feeding and gastric emptying) occurs after the peptide leaves its cell of synthesis by enzymatic action in the circulation.

Effects of different intermittent peptide YY (3-36) dosing strategies on food intake, body weight, and adiposity in diet-induced obese rats.

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+/-10 g body wt, 166+/-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+/-15 vs. 672+/-15 g) and 43% (96+/-7 vs. 169+/-9 g), respectively. The declining inhibitory effect of PYY(3-36) on daily food intake when the interinfusion interval was >or=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.

A new endogenous form of PYY isolated from canine ileum: Gly-extended PYY(1-36).

We purified and identified the peptide YY (PYY) forms present and determined their levels from a portion of the canine ileum directly adjacent to the cecum by a new extraction method designed to prevent and evaluate degradation of endogenous peptides. We used three reverse phase chromatography steps with radioimmunoassay of fractions for PYY-like-immunoreactivity (PYY-LI). The purified fractions underwent intact protein/peptide mass spectrometry identification and sequencing (i.e. "top-down" MS analysis). This analysis confirmed the identity of a new form of PYY, PYY(1-36)-Gly, which co-elutes with PYY(1-36)-NH(2) through all three of separation steps used. The PYY(1-36)-Gly form represents approximately 20% of the total PYY found in this region of the canine intestine. In addition, we also found that the PYY(3-36)-NH(2) form represents 6% of the total PYY in the canine ileo-cecal junction. The physiological implication of the Gly-extended form of PYY(1-36) warrants further investigation.

Effects of intermittent intraperitoneal infusion of salmon calcitonin on food intake and adiposity in obese rats.

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 +/- 10 g body wt, 27 +/- 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 +/- 12 vs. 651 +/- 14 g) and 22% (20.6 +/- 1.2 vs. 26.5 +/- 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.

Comparison of the effects of chronic central administration and chronic peripheral administration of islet amyloid polypeptide on food intake and meal pattern in the rat.

Islet amyloid polypeptide (IAPP) is postulated to act as a hormonal signal from the pancreas to the brain to inhibit food intake and reduce adipose energy reserves. The present study compared the effects of chronic peripheral and chronic central administration of IAPP on food intake and meal pattern in rats. IAPP was administered subcutaneously (SC) for 7 days at doses of 0, 0.25, 2.5 and 25 pmol kg(-1) min(-1) using an osmotic minipump or administered centrally at doses of 0, 0.025, 0.25 and 2.5 pmol kg(-1) min(-1) using an osmotic minipump connected to an intracerebroventricular (ICV) catheter inserted into the third ventricle. Both SC and ICV infusion decreased total food intake dose-dependently. The minimal effective dose was 2.5 pmol IAPP kg(-1) min(-1) for SC administration and 0.25 pmol kg(-1) min(-1) for ICV infusion. The decrease in food intake produced by infusion of IAPP was mainly due to decreased meal size, although a significant decrease in meal number also occurred at the highest SC and ICV doses. SC administration produced a larger, more persistent decrease in food intake during the light period than in the dark period, while ICV infusion caused a larger, more persistent decrease during the dark period. The 10-fold difference in minimal effective doses indicates that ICV-administered IAPP acted primarily in the brain to inhibit food intake. The difference between the effects of IAPP on meal pattern with the two methods of administration suggests that IAPP does not act on the same target(s) when administered centrally as it does when it is administered peripherally.

Intermittent intraperitoneal infusion of peptide YY(3-36) reduces daily food intake and adiposity in obese rats.

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.kg(-1).min(-1) was reduced to 10 pmol.kg(-1).min(-1) on day 10 and then increased to 17 pmol.kg(-1).min(-1) on day 13. This dosing strategy produced a sustained reduction in daily caloric intake of 11-32% and prevented body weight gain (8 +/- 6 vs. 51 +/- 11 g) and fat deposition (4.4 +/- 7.6 vs. 41.0 +/- 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.

Ghrelin attenuates the inhibitory effects of glucagon-like peptide-1 and peptide YY(3-36) on food intake and gastric emptying in rats.

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 x kg(-1) x min(-1)) stimulated food intake by 28% during the infusion period primarily by increasing meal frequency; doses of 15 and 50 pmol x kg(-1) x min(-1) had no effect. GLP-1 (15 pmol x kg(-1) x min(-1)) inhibited food intake by 35-54%; coinfusion of ghrelin at 50 and 150 pmol x kg(-1) x min(-1) attenuated this effect by 60 and 64%, respectively. PYY(3-36) (15 pmol x kg(-1) x min(-1)) inhibited food intake by 32%; ghrelin at 15 and 50 pmol x kg(-1) x min(-1) attenuated this effect by 54 and 74%, respectively. A 20-min intravenous infusion of ghrelin (15-150 pmol x kg(-1) x min(-1)) attenuated GLP-1-and PYY(3-36)-induced inhibition of gastric emptying of saline by 6-29%. Thus, intravenous infusion of ghrelin during the early dark period stimulates food intake in freely feeding rats by increasing meal frequency, and similar doses of ghrelin attenuate gastric emptying and feeding responses to GLP-1 and PYY(3-36). 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.

Dose-dependent effects of peptide YY(3-36) on conditioned taste aversion in rats.

We used a conditioned taste aversion test to assess whether PYY(3-36) reduces food intake by producing malaise. Two-hour IV infusion of PYY(3-36) (8, 15, and 30 pmol/kg/min) at dark onset in non-food-deprived rats produced a dose-dependent inhibition of feeding and a conditioned aversion to the flavored chow paired with PYY(3-36) infusion. In food-deprived rats, PYY(3-36) at 2 and 4 pmol/kg/min inhibited intake of a flavored saccharin solution without producing conditioned taste aversion, whereas higher doses (8 and 15 pmol/kg/min) inhibited saccharin intake and produced taste aversion. These results suggest that anorexic doses of PYY(3-36) may produce a dose-dependent malaise in rats, which is similar to that reported for PYY(3-36) infusion in humans. Previous studies have shown that PYY(3-36) potently inhibits gastric emptying, and that gut distention can produce a conditioned taste aversion. Thus, PYY(3-36) may produce conditioned taste aversion in part by slowing gastric emptying.