Insulin is a prandial satiety hormone.

The present study assessed meal-contingent insulin effects on spontaneous meal patterns. Rats, trained to lever press for daily food requirements, showed stable meal patterns and were then implanted with hepatic-portal catheters. Once again stable in ingestion, animals received either physiological saline or vehicle plus 1 or 2 mU of regular, short-acting insulin beginning at 10 pellets into each initiated meal (which was the chosen minimum meal size definition). All meals during that day were then infused with the same solution and comparisons were made within animals (across days) only. Insulin reduced the size of spontaneous meals at both 1 mU (p < .01) and 2 mU doses (p < .001). No other meal parameters were significantly affected. In a complementary study, rats trained to lever press showed increases in meal size when "recovering from" a diazeoxide-adulterated diet (diazeoxide has been shown to limit insulin release). Thus, when insulin is increased during spontaneously taken meals, those meals are reduced in size and drugs which block insulin release, increase the size of meals; we assert insulin is a prandial satiety hormone which likely reduced feeding by increasing glucose uptake into peripheral tissue.

Lithium chloride and inescapable, unsignaled tail shock differentially affect meal patterns of rats.

Several motivational states, such as malaise, fear, and satiety, reduce spontaneous food ingestion by rats, and differentiation of these states is often desirable. The present study used the spontaneous meal pattern to this end. The illness-inducing toxin lithium chloride delayed initiation of the first postinjection meal, and that meal was smaller and eaten more slowly (Experiments 1A and 1B). Rats exposed to tail shock also subsequently took longer to initiate meals, but meals were eaten faster and were slightly larger relative to control conditions (Experiment 2). These changes in meal patterns are different from those produced by satiety-related hormones, such as CCK or insulin, which solely reduce meal size in paradigms designed to assess physiological regulation of food intake. Taken together, these findings attest to the ability of meal patterns to distinguish malaise, fear, and satiety from one another.

Cholecystokinin and estradiol synergistically potentiate satiety in rats.

The ability of octapeptide cholecystokinin (CCK), in interaction with ovarian steroid conditions, to decrease 1-h feeding was studied in 5-h food-deprived Sprague-Dawley rats. In Experiment 1, intact, unilaterally ovariectomized, and bilaterally ovariectomized females and intact males were given IP injections of 0, 0.25, 0.50, and 1.0 microgram/kg b.wt. CCK and were assessed for food ingestion at 1, 3, and 19 h. Food intake at 1 h was suppressed in animals receiving CCK compared to saline (0 dose); the threshold dosage was 1 microgram/kg b.wt. (p < 0.01) in this paradigm. No significant sex difference was observed between the four groups; however, animals with decreased ovarian steroids (intact males and bilaterally ovariectomized females) suppressed ingestion less than animals with greater ovarian steroid levels (intact and unilaterally ovariectomized females) at both the 0.25 and 1.0 microgram/kg b.wt. dosages (p < 0.01). Therefore, in a second experiment, sensitivity to CCK was compared in females in early metestrus, when estrogen levels are decreased, and during late diestrus, when estrogen levels are high, using dosages of 0, 0.25, 1, and 2.5 micrograms/kg b.wt. A statistically significant difference was found between sensitivity at early metestrus and late diestrus at the 2.5 micrograms/kg b.wt. dose only, with food ingestion more reliably depressed during periods of increased estrogen (p < 0.05). These results suggest that estradiol and CCK can have a synergistic effect on satiety.

Pancreatic glucagon suppresses gustatory responsiveness to glucose.

Peripheral administration of the gut peptide pancreatic glucagon (GGN) alters hepatic metabolism and suppresses feeding. Other physical (gastric distension) and chemical factors (hyperglycemia, hyperinsulinemia) that reduce food intake also suppress taste-evoked activity. This may attenuate the reinforcement derived from feeding and so promote termination of the meal. To determine whether this mechanism was operative with GGN administration, we studied the effect of hepatic portal infusions of 40 micrograms/kg pancreatic GGN on taste responses in the nucleus tractus solitarius of the rat. Taste activity was elicited by oral application of NaCl, glucose, HCl, and quinine HCl. Responses were monitored before and after injections of GGN or a control vehicle. Blood glucose levels were measured in separate groups of GGN- and vehicle-injected rats. Blood glucose increased significantly after GGN infusion and returned to control levels within 35 min. Taste responsiveness to glucose was significantly reduced after the GGN injection and recovered to preinjection levels by 36 min. Activity evoked by NaCl, HCl, and quinine HCl was unaffected. The suppression of responsiveness to sugars may reduce the hedonic appeal of tastants and so serve as a mechanism by which GGN could contribute to postprandial satiety.

Insulin and satiety from feeding in pancreatic-normal and diabetic rats.

Insulin's role in food ingestion and satiety was investigated in streptozotocin-diabetic and pancreatic-normal rats. Markedly diabetic rats (60-65 mg/kg b.wt. streptozotocin with mean glycemia of 380 mg/dl) were observed for daily food/water intake and body weight changes and meal pattern in a standard operant chamber. Diabetic animals showed an immediate hypophagia (days 1-4) by decreasing meal size (MS). As animals lost weight, a significant hyperphagia appeared, accomplished by an elevation in MS. Treatment with insulin infused via osmotic minipump at a stable rate (6.0 U/24 h) reduced polyuria and glycemia, eliminated glycosuria, and restored weight gain. MS did not, however, return to baseline immediately. In a second experiment with milder diabetes (20-22 mg/rat streptozotocin, which produced glycemia ranging from 148 to 304 mg/dl), significant hyperphagia appeared, again attributable to an increase in MS. Minipumps infusing 2.4-4.0 U insulin/24 h reversed this hyperphagia. In pancreatic-normal rats, pumps infusing insulin at 1.2 or 2.4 U/24 h produced a modest hypophagia accomplished by a primary decrease in nocturnal intake (11% suppression in dark feeding). Subdiaphragmatically vagotomized rats showed an attenuation of this suppression (no significant effects on food or water intake produced by insulin infused). Insulin appears to participate in satiety by limiting MS, without significantly shortening latency to take the next meal.

Restrained and nonrestrained eaters' orienting responses to food and nonfood odors.

Dietary restraint was assessed by Stunkard and Messick's (1985) three-factor eating questionnaire, using the restraint subfactor score only in normal-weight college students (n = 41). The subjects were than assessed for skin conductance orienting responses (ORs) to food and nonfood odors when hungry and sated (after a standard breakfast and after an overnight fast). Subjects also rated their hunger and each odorant for pleasantness on separate 7-point scales. Results indicated that restrained eaters oriented less to odors than did nonrestrained subjects. Food deprivation did not differentially affect the ORs in restrained and nonrestrained eaters. The ORs, however, tended to be decreased in all of subjects who had had breakfast. Finally, nonrestrained subjects rated food and nonfood odors approximately equal in pleasantness, while the restrained eaters rated food odors as more pleasant than the nonfood odors. These results suggest that restrained eaters must certainly process odor stimuli related to foods, but also suggests that orienting to these salient (informative) cues is restricted. Perhaps in defense of the diet, restrained eaters learn methods/responses (cognitive strategies, instructional sets) to block orienting to food related cues such as odors.

Vagally mediated feeding responses to phloridzin infusion in the rabbit.

Rabbits were infused with the plant glycoside, phloridzin, which blocks absorption of glucose across a number of bodily tissues. Feeding was dramatically increased in the first 0.5 h following phloridzin infusion into either the duodenum or the hepatic-portal vein of intact rabbits. Food intake covaried inversely with glycemic levels after phloridzin infusion into the hepatic-portal vein, but rabbits did not show a systematic relationship between blood glucose levels and food intake following duodenal infusion of phloridzin. When administered into the general circulation via the jugular vein, phloridzin did not elicit feeding. Finally, vagotomized rabbits did not show the hyperphagic response to phloridzin that was observed in intact rabbits. It was concluded that the feeding response to phloridzin is vagally mediated and appears to be induced by glucose transport inhibition at some peripheral site.

Administration of satiety factors and gustatory responsiveness in the nucleus tractus solitarius of the rat.

The administration of certain factors associated with postprandial satiety decreases gustatory responsiveness. We compared the effects of intravenous injections of glucose, insulin, pancreatic glucagon (PG), and cholecystokinin (CCK) on multiunit activity evoked from taste responsive neurons in the nucleus tractus solitarius of rats. Glucose, insulin, and PG reliably suppressed evoked responses to lingual application of 1.0M glucose, whereas responses that followed CCK remained unchanged. A common physiological consequence of glucose, insulin, and glucagon is increased glucose availability which may impact directly on gustatory neurons or indirectly through modifications in ventral forebrain or vagal afferent activity.

Insulin modifies flavor aversions and preferences in real- and sham-feeding rats.

In separate, parallel experiments, rats were allowed to sham or real feed a flavored sweetened condensed-milk solution after a 17.5-h fast. Coinciding with administration of the milk were injections of insulin or vehicle (saline). Insulin had no effect on intake in the real feeding situation, and flavors paired with insulin (0.8, 2.5, or 5.0 U/rat) were avoided, relative to saline-paired flavors. In sham-feeding rats, insulin (0.8 U/rat) significantly reduced the amount of milk consumed, and flavors paired with insulin injection were preferred, relative to saline-paired ones. Insulin produced a relatively larger hypoglycemia during sham feeding than during real feeding. Thus it appears that insulin-paired flavors of milk may be preferred by animals when they are ingested in sham feeding but not in animals real feeding. Perhaps rapid gastric emptying, as would occur with a liquid diet, accompanied by increased insulin levels, leads to malaise and flavor aversion.

Tolbutamide affects food ingestion in a manner consistent with its glycemic effects in the rat.

The sulphonylurea tolbutamide possesses the ability to stimulate insulin release, produce hypoglycemia and increase food intake; however, no study has investigated the effects of moderate doses which do not produce frank hypoglycemia. Forty male rats received injections of tolbutamide at 0, 5, 15, 25 or 50 mg/kg body weight. The injections terminated a 2-hr fast and occurred at light offset, insuring a meal. Food intakes were then recorded for two hr following injection. Tolbutamide at 5 and 15 mg doses decreased food intake during the first half-hour or hour, respectively. In parallel experiments, 10 rats were sampled for blood prior to injection of tolbutamide or saline at doses cited above, and again at 10 and 40 min following injection in the absence of food. Plasma was then analyzed for insulin and glucose. Both 5 and 15 mg tolbutamide produced a mild, reliable increase in insulin accompanied by a decrease of 5 to 15 mg/dl in plasma glucose. On the other hand, the 50 mg dose produced a marked increase in insulin and a decrease of approximately 25% in plasma glucose. Thus, the present studies suggest that when endogenous insulin levels are modestly raised by tolbutamide, such that only moderate reductions of circulating glucose were observed, decreases in food intake occur.

Phentolamine stimulates insulin release and glucose clearance and suppresses food ingestion.

In Experiment One, phentolamine (PTA), an alpha-adrenergic blocker, was injected in rats at doses of 0, 50, 100, 200, and 300 micrograms/kg following a 4-hr fast. Measurement of food intake 1-hr postinjection revealed that 300 micrograms/kg PTA reduced food intake. Experiment Two evaluated the potential aversiveness of 300 micrograms/kg PTA. Four-hour fasted rats were adapted to a milk diet as the only food source during a 1-hr intake measurement period. After the 15-day adaptation period, three separate groups of animals (n = 8 per group) received the milk with cherry flavoring added and infections of either 1% body weight 0.9 NaCl, isosmotic LiCl or 300 micrograms/kg PTA. Only those subjects that had received LiCl injections developed a reliable aversion to the cherry-flavored milk. The final experiments subdivided the 1-hr feeding period into three 20-min segments and, in separate animals, food intake or plasma insulin and glucose changes were assessed. The animals were assigned to one of two groups receiving either 300 micrograms/kg PTA or equivolume 0.9% NaCl. PTA-injected subjects showed an immediate modest enhancement of insulin release during the first 20-min feeding segment following injection, compared to controls, while blood glucose levels decreased but never differed reliably between groups. Food intake was reliably suppressed in the second and third 20-min segments for the PTA-injected rats. We advance that PTA by enhancing glucose clearance may be reducing ingestion.

Glucagon, satiety from feeding and liver/pancreatic interactions.

In an attempt to assess pancreatic glucagon's efficacy at repeatedly reducing food ingestion during differing circadian periods, three groups of 8 rats each were randomly assigned to 4-hr food deprivations beginning at 0800, 1200 or 1600 with light off at 2000. Subjects were then refed following injections of pancreatic glucagon (400 micrograms/kg b.wt. dissolved in DMSO) or vehicle alone every third day (no injection on intervening day). Food intake was measured at 1 and 20 hr following each injection. Following 3 cycles of the above procedure, each animal was again food deprived at the appropriate time, stunned and sacrificed by decapitation. The liver was sampled and glycogen determinations were made. Glucagon suppressed food intake when injected at 1200 (49.6%) and at 1600 (43.1%) but not when given at 2000 (-2.2%). Glycogen content measured after similar deprivation ending at these times was 5.6, 3.9 and 2.0%, respectively. With repeated glucagon injections, the hormone lost its ability to reduce food intake. In a second study, designed to evaluate the role of insulin in glucagon's action, three groups of 6 rats each were given atropine plus glucagon or glucagon or atropine injections alone; food ingestion was then measured one hr later. Atropine alone somewhat decreased eating, however, in combination with glucagon (given 10 min following atropine), no significant decrements in ingestion were achieved. Glucagon injected after saline produced a significant reduction in food intake (62.5%). Since glucagon stimulates insulin release and hyperglycemia; perhaps insulin release is necessary for glucagon's satiety effect.

Sham feeding, flavor associations and diet self-selection as indicators of feeding satiety or aversive effects of peptide hormones.

We have attempted to develop a constellation of behaviors which show differential effects following the administration of putative satiety hormones (CCK-8, BBS, insulin) as opposed to effects seen following a toxin, such as LiCl. In the initial behavior assessed, sham feeding of differently paired, flavored milks (flavor paired with insulin, BBS or saline) was carried out. Male adult Sprague-Dawley rats which sham fed milk flavors paired with 16 micrograms/kg BBS showed a significant aversion of that flavor in a two-bottle taste test (compared to saline-paired flavors, p less than 0.001) but a significant preference for flavored milk paired with 0.4 and 0.75 U insulin/rat. Lower dosages of BBS (4 and 8 micrograms/kg) and insulin (0.1 U/rat) showed no significant aversion or preference when compared to saline. The second behavioral paradigm evaluated the effects of the hormones CCK-8 and BBS and the toxin, LiCl, upon self-selection of pure macronutrients. While CCK-8 reduced intake of calories by significantly lowering ingestion/selection of fats (55%, p less than 0.01 compared to saline, control injections) and carbohydrates (50%, p less than 0.01), LiCl and BBS reduced calories by decreasing selection of primarily proteins (LiCl--49%, p less than 0.03; BBS--63% at 4 micrograms/kg and 80% at 8 micrograms/kg, both p less than 0.025). In both paradigms then, BBS at doses sufficient to significantly reduce sham intake or suppress caloric ingestion in a self-selection paradigm produced behavioral effects most similar to those observed following the injection of a toxin. LiCl, rather than effects seen following other various putative satiety signals.

Insulin suppresses intake without inducing illness in sham feeding rats.

Insulin's effects on consumption were investigated in rats feeding with open gastric cannulas. Insulin produced small but statistically reliable decreases in sham intake. Intake was reduced during the one-hour sham feeding interval by 11 to 18%, however, the second, third and fourth 15-min intervals were reduced by 20 to 33%. An initial increase (first 15 min of sham feeding) following insulin injection offset somewhat insulin's suppressive effects on sham intake. All reductions were obtained by comparing sham intake following 0.1 to 0.75 U insulin per rat to intake following saline. When insulin or saline injections were paired with alternatively flavored sweetened condensed milk during sham feeding, subjects preferred the insulin-paired flavor in a subsequent two-bottle test. After just 6 complete pairings, insulin-paired, flavored milk was preferred at a ratio of almost six to one. The results indicate the effectiveness of insulin in inhibiting intake in a situation in which the actions of other potential satiety mechanisms are minimized. Additionally, insulin accomplishes this without inducing a flavor aversion for the milk sham consumed.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Sympathetic involvement in the lateral hypothalamic (LH) lesion syndrome was examined. Male rats were surgically or chemically sympathectomized and then given LH lesions. At 24 hr postlesion, lesion-induced hyperglycemia but not hyperthermia was attenuated by splanchnicectomy and celiac ganglionectomy. Hyperthermia but not hyperglycemia was attenuated by adrenal demedullation, adrenalectomy, and neonatal guanethidine treatment. Guanethidine-sympathectomized rats also displayed lower basal temperatures, more perilesion chromatolysis, and severer external symptoms than their controls. No form of sympathectomy affected lesion-induced gastric pathology, plasma gastrin concentrations, or body weight loss. Nor did any sympathectomy influence the recovery of ingestive behavior, daily food intake, the feeding response to 2-deoxy-D-glucose, or body weight maintenance in recovered LH-lesion subjects. These results suggest that sympathetic hyperactivity contributes to some aspects of the acute LH syndrome: Hyperglycemia results from sympathetic outflow to the abdomen, whereas hyperthermia is determined by circulating catecholamines and extraabdominal sympathetic innervation. The results fail to support the hypothesis that chronic increases in sympathetic tone are responsible for the reduced food intake and body weight of the LH-lesion rat.

Meal patterns and glucoprivic feeding in the guanethidine-sympathectomized, adrenodemedullated rat.

The feeding behavior of rats sympathectomized by neonatal administration of guanethidine (GUA) and/or adult adrenal demedullation (MDL) was investigated. GUA treatment tended to decrease body weight gain and food intake, chiefly by decreasing meal size and increasing satiety ratios. It also attenuated the increase in food intake caused by 2-deoxy-D-glucose (2DG; 150, 300, 450 mg/kg, IP) but not by insulin (3, 6, 9 U/kg, IP). MDL altered meal patterns in the same manner as GUA treatment but the effects were of smaller magnitude. It did not influence the response to either glucoprivic challenge. Combined GUA treatment and MDL generally produced additive effects. These results suggest that the major sympathetic influence on feeding is through adrenergic innervation and not circulating catecholamines. The hypothesis that the alteration in feeding patterns produced by ventromedial hypothalamic lesions is due to decreased sympathetic activity was not supported.

The alimentary canal, liver and vagus play a role in short-term feeding: but is the role regulation, correlation, glucostasis or spurious association?

The injection of insulin has been used to produce increased food intake and, when given over a period of time, to produce obesity. The hormone, however, is released in 3 distinct phases when subjects encounter and ingest food and one would expect that insulin release would be a correlate, if not a contributory factor, to satiety. On the other hand, glucagon has been used to suppress food intake, but pancreatic glucagon should be released during the absence of food. The present paper investigates the physiologic function of these hormones and gives evidence that insulin serves as part of the normal sequence of hormonal and neural responses to food intake and does appear to play a contributory, causal role in short-term satiety for food intake.

Sham feeding is inhibited by dietary-induced obesity in rats.

A group of six female, albino rats were maintained on a cafeteria diet of cookies, milk, and elevated-fat (shortening), rat-chow mixture and rat chow while a similar group received only rat chow ad lib for 17 weeks. When the groups differed significantly in mean body weight (obese-387.5 g, controls-287.2 g; p less than 0.001), gastric fistulas were implanted in each animal. After recovery, the rats were adapted to a liquid diet and assessed for sham feeding. Control-fed, normal-body-weight subjects showed substantial sham feeding when ingesting the Vivonex with the fistulas open compared to fistula-closed intake; meal frequency, meal size (apart from the initial meal) and total food intake were significantly increased while the satiety ratios following each meal were significantly decreased. Obese animals showed no significant increased feeding and satiety ratios were unreliably altered; while normal-body-weight controls increased 4-hr food intakes by 93% and halved their mean satiety ratios the obese animals showed an 8% increase in 4-hr food intake and only a 22% decrease in mean satiety ratios. We offer the hypothesis that, when animals are induced to become obese by palatable and varied diets which are then terminated, the anorexia produced is independent of gastrointestinal interactions inasmuch as that anorexia extends to sham feeding.

CCK, endogenous insulin condition and satiety in free-fed rats.

Cholecystokinin (CCK) has been shown to elicit insulin secretion and increased insulin availability has been shown to correlate with increased satiety attributed to reduced size of spontaneously occurring meals. The present experiment, however, clearly showed that CCK was effective in suppressing food ingestion in free-fed rats independent of the animal's level of insulin. Rats were tested with 1, 2 and 4 micrograms/kg of CCK-octapeptide (Sincalide, Squibb) during a baseline (pancreatic-normal) period, an insulin-poor state (streptozotocin diabetic) and an insulin clamped condition (diabetic treated by a minipump). CCK produced a highly significant (p less than 0.01) reduction of food intake compared to saline, control injections regardless of the insulin conditions of the animals. Higher doses of CCK were more effective than lower doses during all three periods of study. CCK and hyperinsulinemia function independently if they produce satiety or reductions in food intake.