Jejunal linoleic acid infusions require GLP-1 receptor signaling to inhibit food intake: implications for the effectiveness of Roux-en-Y gastric bypass

Roux-en-Y gastric bypass surgery results in sustained decreases in food intake and weight loss. A key component is likely the direct delivery of nutrients to the jejunum and resulting changes in levels of gut peptide secretion. Prior work modeling this aspect of the surgery has shown that small-volume, prolonged jejunal infusions of linoleic acid (LA) produce sustained decreases in food intake and weight loss. LA infusions also significantly elevate plasma glucagon-like peptide-1 (GLP-1) levels. To assess a role for the increased circulating GLP-1 in the feeding suppression, we examined the effect of prolonged peripheral minipump administration of the GLP-1 receptor antagonist exendin 9-39 (Ex 9) on the feeding suppression produced by jejunal LA. Using a 2 × 2 design, we infused either saline or LA in the jejunum (7 h/day, 11.4 kcal) for 5 days with a subset of animals from each group receiving either saline or Ex 9 (25 pmol·kg(-1)·min(-1)) continuously via a minipump. The antagonist alone had no effect on food intake. LA reduced daily food intake greatly in excess of the kilocalories infused. Ex 9 completely blocked the feeding suppression produced by the jejunal LA infusion. Ex 9 also attenuated the increase in plasma GLP-1 induced by jejunal LA infusions. These data demonstrate that endogenous GLP-1 receptor signaling is necessary for the reduction in food intake produced by jejunal LA infusions. Whether increased secretion of additional gut peptides is also necessary for such suppressions remains to be determined.     

Nutrient Specific Feeding and Endocrine Effects of Jejunal Infusions

Intestinal nutrient infusions result in variable decreases in food intake and body weight based on the nutrient type and the specific intestinal infusion site. Only intrajejunal infusions of fatty acids decrease food intake beyond the calories infused. To test whether this extra‐compensatory decrease in food intake is specific to fatty acids, small volume intrajejunal infusions of glucose (Glu) and casein hydrolysate (Cas), as well as linoleic acid (LA) were administered to male Sprague–Dawley rats. Equal kilocalorie (kcal) loads of these nutrients (11.4) or vehicle were infused into the jejunum over 7 h/day for five consecutive days. Food intake was continuously monitored and body weight was measured daily. After the infusion on the final day, rats were killed and plasma collected. Intrajejunal infusions of LA and Glu, but not Cas, suppressed food intake beyond the caloric load of the infusate with no compensatory increase in food intake after the infusion period. Rats receiving LA and Glu infusions also lost significant body weight across the infusion days. Plasma glucagon‐like peptide‐1 (GLP‐1) was increased in both the LA and Glu rats compared with control animals, with no significant change in the Cas‐infused animals. Peptide YY (PYY) levels increased in response to LA and Cas infusions. These results suggest that intrajejunal infusions of LA and Glu may decrease food intake and body weight via alterations in GLP‐1 signaling. Thus, particular nutrients are more effective at producing decreases in food intake, body weight, and inducing changes in peptide levels and could lead to a novel therapy for obesity.     

Responses of celiac and cervical vagal afferents to infusions of lipids in the jejunum or ileum of the rat

Multiunit celiac and single-unit cervical recordings of vagal afferents were performed before and during infusions of fatty acids, triglycerides, or saline into either the ileum or jejunum of the rat. In multiunit recordings, lipids increased activity of vagal afferents to a greater extent than saline. The greatest increases in vagal afferent activity resulted from infusions of linoleic acid, conjugated linoleic acid, or oleic acid. The triglycerides, corn oil or Intralipid, were less effective than the fatty acids in affecting vagal afferent activity. Ileal pretreatment with the hydrophobic surfactant Pluronic L-81 significantly attenuated the response of celiac vagal afferents to ileal infusion of linoleic acid. Single-unit recordings of cervical vagal afferents supported the multiunit data in showing lipid-induced increased vagal afferent activity in approximately 50% of ileal units sampled and 100% of a limited number of jejunal units sampled. These data demonstrate that free fatty acids can activate ileal and jejunal vagal afferents in the rat, and this effect can be attenuated by pretreatment with a chylomicron inhibitor. These data are consistent with the view that lipid-induced activation of vagal afferents could be a potential substrate for the inhibitory effects of intestinal lipids on gastrointestinal function, food intake, and body weight gain.     

Effects of 7-day amino acid infusion on renal growth, function, and renin-angiotensin system in fetal sheep

These experiments examined whether renal growth and the fetal renin-angiotensin system could be stimulated by infusion of amino acids and whether chronic amino acid infusions restored glomerulotubular balance, which had been disrupted during 4-h infusions. Five fetal sheep aged 122 +/- 1 days gestation received an infusion of alanine, glycine, proline and serine in 0.15 M saline at 0.22 mmol/min for 7 days. Six control fetuses were given saline at the same rate (5 ml/h). Kidney wet weights after amino acid infusion were 28% larger than control fetuses (P < 0.05), and renal angiotensinogen mRNA levels were approximately 2.6-fold higher (P < 0.005). Circulating renin levels and renal renin mRNA levels were suppressed (P < 0.05), and renal renin protein levels tended to be lower. Arterial pressure was increased, and there was a marked, sustained natriuresis and diuresis. Glomerular filtration rate and filtered sodium were approximately two-fold higher throughout infusion (P < 0.05). Fractional proximal sodium reabsorption, suppressed at 4 h (from 73.4 +/- 6.5 to 53.7 +/- 10.2%), did not return to control levels (36.1 +/- 3.4% on day 7, P < 0.05). Distal sodium reabsorption was markedly increased (from 79 +/- 25 to 261 +/- 75 mumol/min by day 7, P < 0.005), but this was not sufficient to restore glomerulotubular balance. The resultant high rates of sodium excretion led to hyponatremia and polyhydramnios. In conclusion, long-term amino acid infusions increased renal angiotensinogen gene expression, kidney weight, and distal nephron sodium reabsorptive capacity but failed to restore proximal and total glomerulotubular balance.     

Jejunal administration of linoleic acid increases activity of neurons in the paraventricular nucleus of the hypothalamus

The present experiment examined whether neurons located in the paraventricular nucleus of the hypothalamus (PVN) respond to intestinal infusions of long-chain fatty acids. Single-unit recordings were made of neurons located in and adjacent to the PVN during jejunal administration of linoleic acid. Jejunal administration of linoleic acid increased single-unit activity of neurons located in the PVN but did not affect activity of neurons located in adjacent tissue outside the PVN. The largest increases in neuronal activity were observed in the anterior PVN (0.9-1.3 mm posterior to bregma) compared with the posterior PVN (1.8-2.1 mm posterior to bregma). Jejunal administration of saline failed to affect activity of neurons located either inside or outside the PVN. When the same neurons were subsequently tested for their response to intravenous administration of 2 microg/kg of CCK-8, excitatory responses were more frequently observed than inhibitory responses, but both types of responses were observed regardless of whether neurons were located inside or outside the PVN. In addition, there was no strong correlation between the magnitude of the neuronal response evoked by jejunal administration of linoleic acid compared with intravenous CCK-8. These data suggest that neurons located in the anterior PVN may play a role in the mediation of suppression of food intake produced by intestinal administration of lipids.     

Effects of load, and duration, of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men

Enterally administered lipid modulates antropyloroduodenal motility, gut hormone release, appetite, and energy intake. We hypothesized that these effects would be dependent on both the load, and duration, of small intestinal exposure to lipid. Eleven healthy men were studied on four occasions in a double-blind, randomized, fashion. Antropyloroduodenal motility, plasma CCK and peptide YY (PYY) concentrations, and appetite perceptions were measured during intraduodenal infusion of lipid (Intralipid) at 1) 1.33 kcal/min for 50 min, 2) 4 kcal/min for 50 min, and 3) 1.33 kcal/min for 150 min, or 4) saline for 150 min. Immediately after the infusions, energy intake was quantified. Pressure wave sequences (PWSs) were suppressed, and basal pyloric pressure, isolated pyloric pressure waves (IPPWs), plasma CCK and PYY stimulated (all P < 0.05), during the first 50 min of lipid infusion, in a load-dependent fashion. The effect of the 4 kcal/min infusion was sustained so that the suppression of antral pressure waves (PWs) and PWSs and increase in PYY remained evident after cessation of the infusion (all P < 0.05). The prolonged lipid infusion (1.33 kcal/min for 150 min) suppressed antral PWs, stimulated CCK and PYY and basal pyloric pressure (all P < 0.05), and tended to stimulate IPPWs when compared with saline throughout the entire infusion period. There was no significant effect of any of the lipid infusions on appetite or energy intake, although nausea was slightly higher (P < 0.05) with the 4 kcal/min infusion. In conclusion, both the load, and duration, of small intestinal lipid influence antropyloroduodenal motility and patterns of CCK and PYY release.     

The effect of repeated tryptophan administration on body weight, food intake, brain lipid peroxidation and serotonin immunoreactivity in mice

Tryptophan as a circulating precursor of serotonin (5-HT) may suppress food intake and body weight. Tryptophan administration can enhance the generation of reactive oxygen species (ROS) by inducing oxidative pathway in vivo and in vitro. We have examined the effect of repeated tryptophan administration on food consumption, body weight, brain lipid peroxidation and 5-HT immunoreactivity. Tryptophan was given at the dose of 100 mg/kg/24 hr in 0.2 ml saline solution i.p. for 7 days to mice. Control mice received 0.9% NaCL solution at the same manner and volume. Body weights were recorded at the beginning and end of the experiments. Thiobarbituric acid reactive substance (TBARS), the last product of lipid peroxidation, was measured spectrophotometrically. Brain 5-HT levels were determined by the immunohistochemical method. Our findings indicate that the tryptophan suppresses food intake significantly in mice. Body weight decreased and brain TBARS levels increased significantly by repeated tryptophan treatment. Immunohistochemical detection showed that 5-HT levels increased by tryptophan administration. There is a link between increased 5-HT level and oxidative stress by tryptophan administration on brain tissue. Tryptophan at repeated doses should be exercised carefully in clinical practice.     

Comparative effects of the long-acting GLP-1 receptor ligands, liraglutide and exendin-4, on food intake and body weight suppression in rats

The glucagon-like-peptide-1 receptor (GLP-1R) agonists, liraglutide (Victoza) and the synthetic product of exendin-4 (Byetta), are approved for type II diabetes mellitus (T2DM) treatment and may be efficacious in obesity treatment as well, in part, due to the drugs' resistance to enzymatic degradation and prolonged half-life relative to endogenous GLP-1. To address the need to directly compare the food intake- and body weight-suppressive effects of these two GLP-1R ligands, acute and chronic dosing experiments were performed. Once-daily (q.d.) exendin-4 (0, 0.33, 1.5, and 3.0 μg/kg) and liraglutide (0, 50, 100, and 300 μg/kg, q.d.) both reduced the chow intake in nonobese rats in a dose-dependent fashion following either intraperitoneal (IP) or subcutaneous (SC) administration, whereas only liraglutide reduced 24 and 48 h body weight in nonobese, chow-maintained rats. Chow intake and body weight suppression by liraglutide were of greater magnitude and shorter latency following IP compared to SC delivery, whereas for exendin-4, the magnitude of intake-suppression was similar for IP and SC administration. The effects of chronic delivery (7 consecutive days; IP) of liraglutide (25 and 50 μg/kg; q.d.) and exendin-4 (3 μg/kg; q.d. and twice-daily (b.i.d.)) on food intake and body weight were also examined in diet-induced obese (DIO) rats. Liraglutide (50 μg/kg q.d.) and exendin-4 (3 μg/kg b.i.d.) were comparable in suppressing overall high fat/sucrose diet (HFS; 60% kcal from fat) intake. Both drugs regimens yielded marked weight loss over the 7-day period. The weight loss effect of liraglutide was achieved in the first 2 days and remained stable for the duration of the experiment; weight loss with exendin-4 appeared more linear over the 7-day period. In conclusion, administration of the GLP-1R ligands, exendin-4 (b.i.d.) and liraglutide (q.d.), lead to comparable and pronounced suppression of food intake and body weight in DIO rats, suggesting a potential role for these drugs as a clinical tool for obesity treatment.     

Dose-related effects of lauric acid on antropyloroduodenal motility, gastrointestinal hormone release, appetite, and energy intake in healthy men

We recently reported that intraduodenal infusion of lauric acid (C12) (0.375 kcal/min, 106 mM) stimulates isolated pyloric pressure waves (IPPWs), inhibits antral and duodenal pressure waves (PWs), stimulates release of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), and suppresses energy intake and that these effects are much greater than those seen in response to isocaloric decanoic acid (C10) infusion. Administration of C12 was, however, associated with nausea, confounding interpretation of the results. The aim of this study was to evaluate the effects of different intraduodenal doses of C12 on antropyloroduodenal (APD) motility, plasma CCK and GLP-1 concentrations, appetite, and energy intake. Thirteen healthy males were studied on 4 days in double-blind, randomized fashion. APD pressures, plasma CCK and GLP-1 concentrations, and appetite perceptions were measured during 90-min ID infusion of C12 at 0.1 (14 mM), 0.2 (28 mM), or 0.4 (56 mM) kcal/min or saline (control; rate 4 ml/min). Energy intake was determined at a buffet meal immediately following infusion. C12 dose-dependently stimulated IPPWs, decreased antral and duodenal motility, and stimulated secretion of CCK and GLP-1 (r > 0.4, P < 0.05 for all). C12 (0.4 kcal/min) suppressed energy intake compared with control, C12 (0.1 kcal/min), and C12 (0.2 kcal/min) (P < 0.05). These effects were observed in the absence of nausea. In conclusion, intraduodenal C12 dose-dependently modulated APD motility and gastrointestinal hormone release in healthy male subjects, whereas effects on energy intake were only apparent with the highest dose infused (0.4 kcal/min), possibly because only at this dose was modulation of APD motility and gastrointestinal hormone secretion sufficient for a suppressant effect on energy intake.     

Effect of intracerebroventricular angiotensin II on body weight and food intake in adult rats

We recently reported that intracerebroventricular infusions of ANG II decreased food intake and increased energy expenditure in young rats. The aim of the present study was to determine if intracerebroventricular ANG II has similar effects in adult rats. The time course of the effect was also investigated with the idea that at earlier time points, a potential role for increased hypothalamic expression of corticotropin-releasing hormone (CRH) in the anorexia could be established. Finally, the contribution of ANG II-induced water drinking to the decrease in food intake was directly investigated. Rats received intracerebroventricular saline or ANG II using osmotic minipumps. Food intake, water intake, and body weight were measured daily. Experiments were terminated 2, 5, or 11 days after the beginning of the infusions. ANG II (approximately 32 ng.kg(-1).min(-1)) produced a transient decrease in food intake that lasted for 4-5 days although body weight continued to be decreased for the entire experiment most likely due to increased energy expenditure as evidenced by increased uncoupling protein-1 mRNA expression in brown adipose tissue. At 11 and 5 days, the expression of CRH mRNA was decreased. At 2 days, CRH expression was not suppressed even though body weight was decreased. The decrease in food intake and body weight was identical whether or not rats were allowed to increase water consumption. These data suggest that in adult rats ANG II acts within the brain to affect food intake and energy expenditure in a manner that is not related to water intake.     

Effects of maternal leptin treatment during lactation on the body weight and leptin resistance of adult offspring

We investigate whether leptin treatment to lactating rats affects food intake, body weight and leptin serum concentration and its anorectic effect on their adult offspring. Lactating rats were divided into 2 groups: Lep-single injected with recombinant rat leptin (8 microg/100 g of body weight, daily for the last 3 consecutive days of lactation) and control group (C) that received the same volume of saline. After weaning all pups had free access to the control diet, their body weight and food intake were monitored at each 4 days until 180 days of age, when they were tested for its food intake and response to either leptin (0.5 mg/kg body wt, ip) or saline vehicle. The offspring of the leptin-treated dams gained more weight and had higher food intake from day 37 onward (p<0.05), higher amount of retroperitoneal white adipose tissue (RPWAT) (37%, p<0.05) and higher leptin serum concentration (40%, p<0.05) at 180 days of age compared to control group. The food intake at 2, 4, 6 and 24 h was unaffected after acute injection of leptin in these animals, suggesting resistance to the anorectic effect of leptin. The maternal leptin treatment during lactation makes their adult offspring more susceptible to overweight with resistance to the anorectic effect of leptin.     

Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity

Introduction

Maternal obesity is associated with a range of pregnancy complications, including fetal growth restriction (FGR), whereby a fetus fails to reach its genetically determined growth. Placental insufficiency and reduced nutrient transport play a role in the onset of FGR.

Objectives

Metabolomic profiling was used to reveal altered maternal and fetal metabolic pathways in a model of diet induced obesity during pregnancy, leading to reduced fetal growth.

Methods

We examined the metabolome of maternal and fetal livers, and placenta following a high fat and salt intake. Sprague–Dawley rats were assigned to (a) control diet (CD; 1 % salt, 10 % kcal from fat), (b) high salt diet (SD; 4 % salt, 10 % kcal from fat), (c) high fat diet (HF; 1 % salt, 45 % kcal from fat) or (d) high-fat high-salt diet (HFSD; 4 % salt, 45 % kcal from fat) 21 days prior to pregnancy and during gestation. Metabolites from maternal and fetal livers, and placenta were identified using gas and liquid chromatography combined with mass spectrometry.

Results

Maternal HF intake resulted in reduced fetal weight. Altered metabolite profiles were observed in the HF maternal and fetal liver, and placenta. Polyunsaturated fatty acid metabolism was significantly altered in maternal and fetal liver by maternal fat intake.

Conclusion

Excess of linoleic and α-linoleic acid (essential fatty acids) may be detrimental during placentation and associated with a reduction in fetal weight. Additionally, maternal, placental and fetal response to increased fat consumption seems likely to involve palmitoleic acid utilization as an adaptive response during maternal obesity.

     

Suppression of food intake and body weight gain by naloxone in rats

The effect of acute and chronic administration of naloxone on food acquisition and weight gain in rats was studied in 3 experiments. One injection of a sparingly-soluble salt of naloxone in slow-release vehicle markedly lowered mean food intake over that of control rats injected with the vehicle only. Mean body weight of the naloxone-injected rats was significantly lower than that of the control group for one week.Repeated evening injections (2000 h) of naloxone hydrochloride in saline tended to reduce the night-time feeding below control levels throughout the 10-day period of naloxone administration. Food intake was significantly lower in the 4- and 8-h periods after the first injection of naloxone than that on the preceding saline control night. The initial decreases were offset by increased day-time feeding so that total daily food intake was not significantly altered over the 10 days. When saline was substituted for naloxone, food intake increased.Rats given naloxone following 24 h of fasting consumed significantly less food and gained less weight during 4 h of access to food compared to those receiving saline. After a 48-h fast naloxone-treated rats also gained significantly less body weight than those given saline, but the reduction in food intake was not statistically significant. These results suggest the possibility that endorphins may have a modulating effect on feeding activity.     

Energy flux, more so than energy balance, protein intake, or fitness level, influences insulin-like growth factor-I system responses during 7 days of increased physical activity.

The purpose of this study was to determine the impact of dietary factors and exercise-associated factors on the response of IGF-I and its binding proteins (IGFBPs) during a period of increased physical activity. Twenty-nine men completed a 4-day (days 1-4) baseline period of a controlled energy balanced diet while maintaining their normal physical activity level followed by 7 days (days 5-11) of a 1,000 kcal/day increase in physical activity above their normal activity levels. Two subject groups, one sedentary (Sed, mean Vo(2peak): 39 mlxkg(-1)xmin(-1), n = 7) and one fit (FIT1, mean Vo(2peak): 56 ml.kg(-1)xmin(-1), n = 8) increased energy intake to maintain energy balance throughout the 7-day intervention. In two other fit subject groups (FIT2, n = 7 and FIT3, n = 7), energy intake remained at baseline resulting in a 1,000 kcal/day exercise-induced energy deficit. Of these, FIT2 received an adequate protein diet (0.9 g/kg), and FIT3 received a high-protein diet (1.8 g/kg). For all four groups, IGF-I, IGFBP-3, and the acid labile subunit (ALS) were significantly decreased by day 11 (27 +/- 4%, 10 +/- 2%, and 19 +/- 4%, respectively) and IGFBP-2 significantly increased by 49 +/- 21% following day 3. IGFBP-1 significantly increased only in the two negative energy balance groups, FIT2 (38 +/- 6%) and FIT3 (46 +/- 8%). Differences in initial fitness level and dietary protein intake did not alter the IGF-I system response to an acute increase in physical activity. Decreases in IGF-I were observed during a moderate increase in physical activity despite maintaining energy balance, suggesting that currently unexplained exercise-associated mechanisms, such as increased energy flux, regulate IGF-I independent of energy deficit.     

Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that shows promise for the treatment of short bowel syndrome (SBS). Our objective was to investigate how combination GLP-2 + enteral nutrients (EN) affects intestinal adaption in a rat model that mimics severe human SBS and requires parenteral nutrition (PN). Male Sprague-Dawley rats were assigned to one of five groups and maintained with PN for 18 days: total parenteral nutrition (TPN) alone, TPN + GLP-2 (100 μg·kg(-1)·day(-1)), PN + EN + GLP-2(7 days), PN + EN + GLP-2(18 days), and a nonsurgical oral reference group. Animals underwent massive distal bowel resection followed by jejunocolic anastomosis and placement of jugular catheters. Starting on postoperative day 4, rats in the EN groups were allowed ad libitum access to EN. Groups provided PN + EN + GLP-2 had their rate of PN reduced by 0.25 ml/day starting on postoperative day 6. Groups provided PN + EN + GLP-2 demonstrated significantly greater body weight gain with similar energy intake and a safe 80% reduction in PN compared with TPN ± GLP-2. Groups provided PN + EN + GLP-2 for 7 or 18 days showed similar body weight gain, residual jejunal length, and digestive capacity. Groups provided PN + EN + GLP-2 showed increased jejunal GLP-2 receptor (GLP-2R), insulin-like growth factor-I (IGF-I), and IGF-binding protein-5 (IGFBP-5) expression. Treatment with TPN + GLP-2 demonstrated increased jejunal expression of epidermal growth factor. Cessation of GLP-2 after 7 days with continued EN sustained the majority of intestinal adaption and significantly increased expression of colonic proglucagon compared with PN + EN + GLP-2 for 18 days, and increased plasma GLP-2 concentrations compared with TPN alone. In summary, EN potentiate the intestinotrophic actions of GLP-2 by improving body weight gain allowing for a safe 80% reduction in PN with increased jejunal expression of GLP-2R, IGF-I, and IGFBP-5 following distal bowel resection in the rat.     

Influence of different dietary concentrations of linoleic acid on the essential fatty acid (EFA) status and functional characteristics of porcine hepatic and cardiac mitochondria

The effect of different dietary concentrations of linoleic acid (0.2, 1.1 and 2.1% of gross energy in experiment 1 and 0.7, 1.6 and 2.3% of gross energy in experiment 2) on the EFA status and the functional characteristics of hepatic and cardiac mitochondria was investigated in pigs raised for 140 days from 10 to 105 kg live wt on their respective diets. As judged from the ratios of 20:3n9 to 20:4n6 of hepatic and cardiac mitochondrial total lipids the pigs receiving 0.2% of dietary gross energy as linoleic acid were EFA-deficient, while the pigs receiving 0.7% of dietary gross energy as linoleic acid were on the borderline of EFA deficiency. Mitochondrial protein yield and the functional parameters (endogenous respiration, respiration of exogenous NADH, state 2, 3 and 4 respiration, RCI-values, ADP/O ratios and synthetic rates of ATP) as measured in both hepatic and cardiac mitochondria with two substrates pyruvate plus malate and succinate in the presence of rotenone were not significantly (P greater than 0.05) affected by the different dietary concentrations of linoleic acid. The findings indicate a slow turnover of EFA and a low desaturation/elongation activity of the associated enzymes in the pig.     

Cannabinoid-1 receptor antagonists reduce caloric intake by decreasing palatable diet selection in a novel dessert protocol in female rats

Although many feeding protocols induce obesity, few use multiple foods to analyze diet selection within a single group of animals. To this end, we describe a protocol using time-limited access to a dessert that induces hyperphagia and body weight gain while allowing simple analysis of diet selection. Female retired breeder Sprague-Dawley rats were provided with ad libitum access to standard moist chow (1.67 kcal/g) and daily 8-h nocturnal access to either a sugar gel (SG; 0.31 kcal/g) or sugar fat whip (SFW; 7.35 kcal/g) for 15 days, and food intake and body weight were measured daily. Rats given SFW reduced moist chow intake but not enough to compensate for the large amount of calories consumed from SFW, and thus gained weight. We use this SFW overconsumption protocol to investigate the hypothesis that cannabinoid (CB)1 receptor antagonists reduce caloric intake by selectively decreasing consumption of palatable foods. In two experiments, female retired breeder Sprague-Dawley rats were injected with either Rimonabant (1 mg/kg ip) or vehicle (equal parts polyethylene glycol and saline, 1 ml/kg ip) for 7 days, or one of three doses of AM251 (0.3, 1.0, or 3.0 mg/kg ip), or vehicle for 15 days; food intake and body weight were measured daily. Both Rimonabant and AM251 decreased 24-h caloric intake, but the reduction was specific to a decrease in SFW consumption. This supports the hypothesis that these CB1 receptor antagonists impact feeding by modulating the perception of palatability.     

Action of anorexigenic peptide injected into the brain: Dissociation of effect on body weight and feeding in the rat

Previous reports on the effect of anorexigenic peptide (AXP) administered systemically in the rodent are inconsistent in terms of the effect of the tri-peptide on food intake and body weight. The purpose of this study was to examine the effect of AXP infused into the brain on these measures. In post-pubescent female rats of the Sprague-Dawley strain, guide cannulae were permanently implanted in the lateral cerebral ventricle for repeated intracerebroventricular (ICV) infusion. Postoperatively, measures of food and water intake and body weight were obtained every day at the same time. After a 7-day base-line period, AXP was infused bilaterally in a total volume of 15 μl and in a dose of either 0.25 μg (n=7) or 1.25 μg (n=5), with artificial CSF vehicle serving as the control solution (n=6). ICV infusions were given once daily for 20 consecutive days, after which the same intake and body weight measures were recorded for another 7-day period. The rats given 0.25 μg AXP showed a significant suppression in weight gain with the overall slope of the growth curve being 0.358. In contrast, the growth slope of the rats given the 1.25 μg dose of AXP was 0.621, whereas those given the CSF was 0.823. Although the trends of intake of food tended to follow the curves of the rats' body weight, the difference between g/kg food intake of rats during ICV infusions of either dose of AXP was not significantly different from that of the CSF controls. Water intake also was unaffected by either dose of AXP. These results demonstrate that this tri-peptide derived from urine of patients afflicted with anorexia nervosa exerts a direct effect on the brain. Since the 0.25 μg dose of AXP infused acutely ICV caused a sustained hyperthermia, its mechanism of action is apparently a metabolic one; that is, the interruption in the gain in body weight of the rat is independent of the amount of food it ingests.     

Relationship between increasing duodenal lipid doses, gastric perception, and plasma hormone levels in humans

Duodenal lipid causes gastric relaxation, CCK secretion, and nausea. Vasopressin has been implicated in motion sickness-related nausea. We hypothesized that increasing doses of lipid enhance gastric relaxation and CCK-vasopressin secretion, resulting in a dose-related exacerbation of nausea. Nine healthy subjects received isotonic saline or lipid (1, 2, or 3 kcal/min, L1, L2, L3) duodenally. Changes in gastric volume, sensations, and plasma hormone levels were assessed during infusions and isobaric gastric distensions. Lipid infusions increased gastric volume, plasma CCK (but not vasopressin) levels, and gastric compliance during distensions, compared with saline. Plasma CCK levels were related to the dose of lipid administered [CCK levels at 30 min (pmol/l), saline: 1.1 +/- 0.2, L1: 1.8 +/- 0.2, L2: 3.0 +/- 0.2, L3: 4.3 +/- 0.6]. During distensions, nausea increased in intensity with increasing doses of lipid [score (where 0 is no sensation and 100 is strongest sensation), saline: 7 +/- 4, L1: 19 +/- 7, L2: 44 +/- 7, L3: 66 +/- 8]; however, no further rise in plasma CCK occurred. Because neither lipid nor distension alone induced significant nausea, we conclude that the interaction between these stimuli together with a modulation by CCK is responsible for the effects observed. Vasopressin is not involved in lipid- and distension-induced nausea.