Preference enhancement for alcohol by passive exposure.

A large and lasting enhancement of alcohol consumption over control levels is reported after direct infusion of 10 percent alcohol into the stomach of rats for 6 days.

Satiety signals from the gastrointestinal tract.

Experiments in rats with crossed intestines have shown that signals arising in a 30 cm segment of upper small intestine do not affect the short-term control of food intake. The combined stimulus of neural and hormonal signals arising in the crossed intestinal segment and of absorbed food do not inhibit intake during a subsequent meal. The relevant satiety signals must arise in either the stomach and upper duodenum or in the lower small intestine. A transplanted stomach study has shown that a hormone released from the stomach is responsible for the termination of a single meal. Other studies show that neural or hormonal signals coming from the lower small intestine are important in the regulation of total daily food intake and in the long-term regulation of body weight.

The effects of specified chemical meals on food intake.

Rats received intragastric infusions of various specified chemical meals and were subsequently tested for a reduction in food intake. A second experiment, using a novel technique, tested for conditioned aversion to the meal infusions. The nonnutritive substances, kaolin clay and emulsified fluorocarbon, had no significant effect on food intake. Infusions of 1 M glucose and 1 M sorbitol reduced feeding behavior, but the 1 M sorbitol infusion also produced a conditioned aversion to flavored pellets paired with the sorbitol infusion, showing that the reduced feeding could have been caused by discomfort. Infusion of a high-fat meal consisting of emulsified triolein mixed with small amounts of sugar and protein or the rat's normal liquid diet, Nutrament, also reduced food intake, and both infusions failed to produce a conditioned aversion. The use of specified meals to understand the chemical basis of satiety requires a sensitive behavioral test to establish that the meal does not cause discomfort or other nonspecific effects.

The effects of ileal transposition on food intake and body weight loss in VMH-obese rats.

Rats were made obese by VMH knife-cuts and then a 5 or 10 cm segment of terminal ileum was transposed to the duodenum. After surgery, the food moved from the stomach into upper duodenum and then traveled through the transposed ileal segment to lower duodenum and continued down the remaining normal digestive tract. Ileal transposition caused a significant reduction in food intake and a substantial loss of body weight. There was no difference in weight loss with 5 and 10 cm ileal transpositions in obese rats, but weight loss was much less in lean rats. Weight loss was accompanied by a considerable loss in dissectable body fat and an increase in the actual weight of the pancreas and small intestine. These changes are probably caused by the unusual stimulation of a short segment of terminal ileum with undigested food and pancreatic enzymes and may have been mediated by the release of ileal hormones. Changes in plasma levels of metabolites, intracellular enzymes, and protein are presented and the importance of this surgery for the treatment of human obesity is evaluated.

Internal signals cause large changes in food intake in one-way crossed intestines rats.

Fifteen pairs of parabiotic rats had either a surgical operation in which a 15 or 30 cm segment of upper small intestine was disconnected from the digestive tract of one rat in the pair and reconnected to the transected duodenum of its partner or had control surgery. Food eaten by one rat in the pair went to the rat's own stomach, traveled through 5 cm of its upper duodenum and then crossed into the isolated segment of the partner's small intestine. After traversing the 15 or 30 cm isolated segment, the remaining unabsorbed food crossed back into the lower duodenum of the rat that fed. Food eaten by the partner went through its own digestive tract, but bypassed the isolated segment of its own upper small intestine. The operation produced a large and sustained change in food intake of both rats in a pair. For the rats with 30 cm crossed segments, the rat that lost intestinal chyme into its partner ate 3.6 times as much food as did its partner for a period of many months. At sacrifice, the rats that ate more, weighed less and had less body fat. These large changes in food intake may be caused by internal changes associated with changes in the amount of food absorbed into each rat or by differential stimulation of the lower digestive tracts. The results clearly show that there is a major internal control mechanism for the amount of food eaten.

Changed central and peripheral catecholamines and indoleamines in one-way crossed-intestine rats: relationship to changes in feeding behavior and metabolism.

The involvement of central and peripheral catecholamines and serotonin (5-HT) in regulation of feeding and energy metabolism was examined in one-way crossed intestine rats that show large and sustained changes in daily food intake. Five to six weeks after the crossed-intestinal surgery, catecholamines and indoleamines in dissected major brain regions and in the heart, intrascapular brown adipose tissue (IntBAT), pancreas, and serum were determined using HPLC with electrochemical detection. The food-losing rats increased daily food intake from 70.8 to 126.3 g, whereas their partners decreased daily food intake from 67.1 to 38.7 g (p < .001). Compared with the partners and sham-operated controls, the food-gaining rats had increased 5-hydroxy-indoleacetic acid (5-HIAA) throughout the brain [hypothalamus, 442.9 vs. 383.5 (p < .05) and 404.2 ng/g (p < .05), Lateral cortex plus amygdala (LC + A), 236.6 vs. 216.8 (p < .05) and 212.0 ng/g (p < .05), brain stem, 282.9 vs. 238.7 (p < .05) and 245.1 ng/g (p = .05), cerebellum, 56.7 vs. 49.6 (p < .05) and 44.4 ng/g (p < .05)]. Higher 5-HIAA in food-gaining rats that were undereating are consistent with serotonin's role in inhibiting food intake. Peripherally, the rats gaining food showed significantly lower NE, 5-HT, and 5-HIAA in IntBAT compared with their partners (NE, 994.2 vs. 1236 ng/g, 5-HT 338.0 vs. 527 ng/g, and 5-HIAA, 39 vs. 51 ng/g). Because NE and 5-HT have been shown to exert stimulating effects on BAT-mediated thermogenesis, lower levels of NE, 5-HT, and 5-HIAA in IntBAT of food gaining rats are compatible with the lower metabolic rate observed in these animals. The results show that both central and peripheral catecholamines and serotonin are involved in regulation of food intake and energy metabolism.

Large changes in food intake in diabetic rats fed high-fat and low-fat diets.

Groups of male Sprague-Dawley rats were predominantly fed either a high-fat or a high-carbohydrate (CHO) diet. For designated 2-day periods, their diets were switched. After baseline measurements of food and water intake, the rats were made diabetic by injections of either 40 or 46-50 mg/kg streptozotocin. Food and water intake gradually increased over a 15-day period for rats on the CHO diet. Whenever the diets were switched, many of the rats showed large changes in food and fluid intake. Body weight showed a gradual decline, but the rats retained half of the dissectable abdominal body fat at sacrifice. Measurements of plasma glucose, insulin and glucagon proved that the rats were diabetic. The changes in average food intake were reasonably consistent with the "utilizable fuel" theory for the control of food intake assuming that the CHO component of each diet was non-utilizable. The distribution of the fat/CHO utilizable fuel ratio in both experiments was flat and non-normal showing that some rats ate as much of the high fat diet as the high CHO diet. Other rats tended to avoid the high fat to an extent that was greater than predicted by the theory, suggesting that the fat diet may have caused malaise. Thus, the individual rat data did not provide strong support for the "utilizable fuel" theory.

Does the integrated level of all plasma nutrients control daily food intake?

Studies on two different types of one-way crossed-intestines rats have shown that daily food intake is controlled by either endogenous gut signals or absorbed nutrients and their metabolic consequences, or both. If the amount of incoming ingested food is metered somewhere in the body, this could only occur in the gut or liver. The capacity of the liver to determine the amount of water-soluble nutrient absorbed was assessed by portacaval shunt and found to be inadequate. Infusion of nutrients directly into the bloodstream show that plasma nutrients provide part of the signal that inhibits daily food intake, but that endogenous gut signals must play some role. Insulin, an important hormone in the movement of plasma nutrients into cells, was found to stimulate food intake at low infusion doses. IV nutrients raise the level of plasma nutrients and lower daily food intake, while insulin, which inhibits the release of endogenous fuels and moves exogenous fuels into cells, lowers plasma nutrients and stimulates daily intake. Thus, the integrated level of all plasma nutrients may be a major controller of daily food intake.

The role of jejunal signals in the long-term regulation of food intake in the rat.

The significance of the upper small intestine in long-term regulation of food intake was investigated in pairs of parabiotic rats in which a 30 cm transected segment of each rat's intestine was sewn into continuity with the intestine of its partner. In this preparation, food eaten by one rat passes through its own stomach and 5 cm of its duodenum and then moves into the partner's intestine. The food traverses the 30 cm segment of the partner's intestine before returning to its own lower small intestine. All pairs were fed a liquid diet 11 hr/day. When the regular diet was diluted 1:1 with water, all rats showed a significant, nearly compensatory increase in their daily intake. In contrast, when only one rat in each pair was fed, thereby depriving it of intrajejunal input from its fasted partner, there was no significant increase in its food intake for about six days, followed by a gradual increase which was never fully compensatory as shown by continued loss of weight for the pair. Feeding rats could not be trained to notice the loss of intrajejunal input by making such loss coincident with a change in diet flavor. Jejunal satiety cues arising from a 30 cm segment, if they exist, do not seem to play a significant role in long-term regulation of food intake.

Comparison of gastric, duodenal and jejunal contributions to the inhibition of food intake in the rat.

Rats equipped with tubes leading to their stomach, duodenum or jejunum were infused with a liquid diet for 9 hr (4 ml/hr) and were allowed to eat during the last 8 hr of infusion. All rats ate significantly less on diet infusion days than on saline or no infusion days. A second study showed that a taste aversion could not be conditioned to flavored water associated with diet infusion. Apparently, intrajejunal injection of nutrients produces satiety and not discomfort. Infusion of the diet for 5 consecutive days into the stomach, duodenum or jejunum consistently and significantly lowered food intake by reducing meal size, not meal frequency. Results suggest that the small intestine below the infusion site contributes to normal satiety.

Effect of intravenous nutrient infusions on food intake in rats.

To assess the effect of gut signals on food intake two types of nutrients were infused intravenously for 17.5 hours in 17 hour fed rats. In the first experiment a solution of 25% d-glucose and 4.25% amino acids (Travasol) was infused at levels of 26 and 52 kcal/day for two consecutive four-day periods. During infusion periods, food intake was reduced from saline baseline levels by 18.9 +/- 1.7 and 34.8 +/- 1.8 kcal/day, respectively. This represents an oral intake reduction of approximately 70% of the infused calories. In contrast, food intake was reduced 17.4 +/- 1.7 kcal/day below saline baseline levels when 40 kcal of Nutralipid were infused. The reduction in food intake was only 43% of the lipid calories infused. These results indicate that infusions of glucose and amino acids are more effective than infusion of fats in inhibiting daily food intake, that gut signals associated with absorption of fat provide important satiety signals and that removal of fat from the bloodstream has relatively little effect on daily food intake.

Food intake after intragastric meals of short-, medium, or long-chain triglyceride.

Food-deprived Sprague-Dawley rats were given equicaloric intragastric infusions of mixed meals consisting largely of short- (SCT), medium- (MCT), or long-chain triglyceride (LCT). When animals were allowed to feed 20 min after infusion, there was an immediate reduction of food intake that was sustained over the 2 hr feeding period. During the first hour of feeding, the SCT, which is digested and absorbed more rapidly than the MCT or the LCT, was more effective per calorie in reducing food intake than these longer-chain triglycerides. However, during the second hour, cumulative intakes after the different triglyceride infusions were not significantly different. Equicaloric infusions of the MCT and the LCT resulted in equivalent reductions of food intake at all times. The satiety effects of these two triglycerides appear to be related to their caloric properties rather than to chain length. Since the LCT reduced food intake before the absorbed fat could have entered the blood to stimulate satiety signals, this satiety effect may be mediated by a gastroenteric signal. None of the triglyceride infusions resulted in a conditioned taste aversion suggesting that food intake was reduced through normal satiety rather than through discomfort.

Morphological and metabolic changes associated with large differences in daily food intake in crossed-intestines rats.

Twenty-two inbred male Lewis rats were made into parabiotic pairs and 7 pairs had a further operation in which the small intestines of the 2 rats were connected so that one rat continually lost food into the upper small intestine and bloodstream of its partner. As a result, these rats showed large and sustained changes in daily food intake with one rat (A) in each pair eating more than twice as much as its partner (B) for the rest of their lives. Measurements of plasma levels of glucose, insulin, and glucagon did not vary directly with daily food intake, but integrated plasma lactate values were lower in rats that ate more (A) and higher in rats that ate less (B). At sacrifice, the rats that ate more were found to have less fat with reduced fat cell size but the same cell number in both retroperitoneal and epididymal fat pads. Measurements of the rate and pattern of glucose metabolism in retroperitoneal fat cells with or without insulin stimulation were similar across groups. Rates of lipolysis with and without epinephrine did not differ among groups. Lipoprotein lipase varied directly with fat cell size and indirectly with daily food intake. These studies show that daily food intake varies directly with fat cell size and inversely with plasma lactate and retroperitoneal lipoprotein lipase levels.

Aversive consequences of jejunoileal bypass in the rat: a conditioned taste aversion analysis.

Jejunoileal bypass (JIB) surgery reduces food intake and body weight in obese humans and rats. Human bypass patients report visceral discomfort following surgery, and the present study assessed the aversive consequences of JIB in rats using a conditioned taste aversion paradigm. In Experiment 1 rats given a cherry-flavored solution immediately after JIB surgery subsequently displayed a strong aversion to the cherry flavor compared to Bypass and Sham-Bypass control groups. Rats in Experiment 2 were familiarized with cherry solution prior to surgery and they did not display an aversion to the solution after receiving a JIB. In Experiment 3, Bypass rats who developed a cherry flavor aversion after JIB subsequently lost this aversion following reconnection of their intestinal tract. The rats in Experiment 4 displayed an aversion to a saccharin-flavored chow that was eaten shortly after JIB surgery, although the aversion was not as pronounced as that obtained with the cherry solution. The results suggest that JIB produces a persisting malaise in rats that may contribute to the feeding and weight inhibitory effects of the operation.

Insulin increases the daily food intake of diabetic rats on high and low fat diets.

The effects of insulin dose and diet composition on daily food intake were investigated by IV infusion of insulin in doses of 2 to 5 U/day into diabetic rats consuming either a high CHO or high fat diet. The daily food intake of the diabetic rats on both diets increased significantly over baseline levels (p < .01) at the low insulin doses and was maintained at these elevated levels through the 5 U/day dose. Insulin increased the rate of weight gain from Ig/day during baseline to 2 and 2.5 g/day in high CHO and high fat fed diabetics (p < .01). These results show that treatment of diabetic rats with continuous low doses of IV insulin results in a 40% increase in daily food intake regardless of the diet consumed and this increase is accompanied by an increase in rate of body weight gain. While the high fat fed diabetics were relatively hypoglycemic, these increases in intake are not the result of insulin-induced hypoglycemia, since blood glucose concentrations are significantly elevated when the increases occur at the lower insulin doses (p < .01). Thus, peripheralinsulin infused at physiological levels stimulates rather than inhibits daily food intake.

Hepatic portal and vena cava insulin infusion increase food intake in diabetic rats.

To test whether the route of insulin delivery has a major effect on the increase in daily food intake associated with chronic insulin treatment, insulin was continuously infused into either the vena cava (VC) or the hepatic portal (HP) vein of 23 diabetic Lewis rats. Increasing insulin doses in both the VC (2 to 6 U/day) and HP (1.5 to 3.5 U/day) groups significantly increased daily food intake (p < .05). Intake was higher in the VC group at 3 U/day but not at 2U/day. When insulin was delivered at a low fixed dose, daily food intake of both the VC and HP groups only increased after urinary glucose losses increased. The rate of weight gain increased significantly in the VC varied group (p < .05). Insulin administration also increased energy expenditure (p < .01). These results suggest that the extent of the increase in daily food intake and body weight that occurs with peripheral exogenous insulin administration is dependent on the route of infusion.

The effects of glucose or lipid infused intravenously or intragastrically on voluntary food intake in the rat.

Glucose or lipid was infused intravenously (IV) or intragastrically (IG) 30 min before and also during the 17 h when rats were fed both a high-carbohydrate diet and a high-fat diet. Three-day infusions of 28.1 kcal of glucose reduced daily food intake by 19.7 +/- 1.9 kcal/day, representing an oral intake reduction equivalent to 70% of each calorie infused. Infusions of 28.1 kcal of lipid reduced baseline food intake by 11.2 +/- 2.7 kcal/day or 40% of each calorie infused (p < 0.0005). Furthermore, infusions of nutrient IG reduced baseline food intake by 17.6 +/- 2.1 kcal/day or 63% of each calorie infused, and infusions of nutrient IV reduced baseline food intake by 13.7 +/- 2.6 kcal/day or 49% of each calorie infused (p < 0.05). Also, glucose infusions (1.0 kcal/40 min) reduced 10-min food intake from saline baseline levels by 1.1 +/- 0.5 kcal, but lipid infusions had no effect. Infused glucose is more effective than lipid in inhibiting short-term intake, daily food intake, and intake of high-carbohydrate diet, and IG infusion is more effective than IV infusion in inhibiting daily food intake.

Insulin infusion stimulates daily food intake and body weight gain in diabetic rats.

Current theories state that physiological levels of insulin inhibit daily food intake and reduce body weight. To test whether insulin induces satiety, systematically increasing doses of insulin from 2.0 to 5.0 U/day were infused intravenously into streptozotocin-induced diabetic rats. Food intake increased significantly from 70.0 +/- 1.4 kcal/day during the saline baseline up to 102.2 +/- 1.9 kcal/day in the 3.5 U/day insulin infusion and then stabilized at 95.9 +/- 0.5 kcal/day for the remaining doses (p less than 0.05). Retained energy values (kcal of food intake minus kcal of urinary glucose loss) also increased from 69.9 +/- 1.4 kcal/day to stabilize at 95 kcal/day (p less than 0.001). Food intake and retained energy of normal controls remained unchanged at 75.4 +/- 1.6 kcal/day for the duration of the study. With elevated food intake and retained energy values after the 3.5 U/day insulin dose, the diabetic rats gained more weight than the normal controls (p less than 0.01). Contrary to expectations, increasing the amount of insulin infused through the physiological range results in a 40% increase in daily food intake and a rapid gain in body weight.

The effects of ileal transposition and jejunoileal bypass on food intake and GI hormone levels in rats.

Male Wistar rats received three different types of small intestinal surgery. Two groups of rats had either 10 or 20 cm of lower ileum transposed to mid-duodenum. A third comparison group of rats had 85% jejunoileal bypass. All three experimental groups showed a sustained post-operative reduction in food intake and a change in body weight gain. Measurements made 36 days after surgery showed that all experimental groups had a large increase in basal and meal-stimulated enteroglucagon. The total-integrated plasma levels of gastrin, GIP, insulin and blood glucose were significantly reduced. At sacrifice, there were large increases in the wet weight of the small intestine and pancreas. These changes were probably due to the chronic stimulation of the lower ileum with nutrient-rich chyme and may be due to the release of ileal hormones.