visceral factors in the control of food intake

~rrrin Rr.\errr~~h BullPritr, Vol. 14, pp. 687-692, 1985. ” Ankho International Inc. Printed in the U.S.A. 0361-9230185 $3.00 + .OO

Visceral Factors in the Control of Food Intake

STRICKER, E. M. AND M. J+ MCCANN. Viscemtj~tctors in thr control off&d intake. BRAIN RES BULL 14(6)687-69X 1985.-Some years ago, we reported that the increased food intake of hy~~ycemic rats was in~bited by the intravenous infusion of fructose, a sugar that cannot cross the blood-brain barrier and nourish cerebral chemoreceptors. More recent experiments therefore have focused on visceral factors in the control of food intake. Three observations have been emphasized in this review. First, we found that gastric emptying was increased during insulin-induced hypoglycemia, and that this effect also was eliminated by administration of fructose. Hepatic vagotomy abolished both this effect of fructose on gastric emptying and its effect on food intake. Second, we found that in rats with severe diabetes, the rate of gastric emptying did decrease in proportion to increasing concentration of an administered glucose load, as it does in intact rats, but calories emptied more rapidly than normal regardless of the concentration of the load. Third, we found that rats with varying degrees of streptozotocin-induced damage to the pancreas ate more food than intact rats did after an overnight fast, and that individu~ intakes were proportional to the induced glucose intolerance.The increased eating took the form of shorter intermeal intervals, as if the initial postfast meal did not remain satiating for a normal amount of time. These and other findings suggest that food intake is controlled in part by satiety signals apparently related to the delivery of utilizable calories plus insulin to the liver. These signals also seem to affect gastric emptying and thereby might influence other satiety signals related to gastric distention.

Food intake Gastric emptying Glucoregulation Hunger Satiety

LIKE other behaviors, food intake is controlled by the brain. For years workers concerned with this aspect of brain function have focused on two regions thought to control food intake, an “appetite center” in the ventrolateral hypothalamus and a “satiety center” in the ventromediai hy- p~~thalamus [ l,S]. Specific controls of food intake involving glucoregulation and lipid regulation also were proposed to be found in the hypothalamus [19,25], thus providing for short-term maintenance of glucose utilization and long-term maintenance of body weight. However, in recent years the well-known effects of hypothalamic lesions on food intake have been interpreted and the dual center model deempha- sized 129,441. Consequently, during this time there has been increasing attention paid to alternative theories that were not rooted in hypothalamic function, many of which have focused instead on visceral factors in the control of food intake. This new perspective began with Russek’s proposal that the origin of signals for hunger and satiety might be found in the liver, not the brain [32]. Later work by Davis and colleagues [S], showing that blood-borne factors might mediate satiety, and by Smith and colleagues [2,I5], suggesting that the intestinal peptide cholecystokinin might be a satiety hormone, added further impetus to a new focus on the problem that provided the context for our own studies of food intake in rats. This chapter briefly reviews that work and discusses our present views of how central and peripheral factors might combine to provide an integrated control of feeding.

GLUCOSTATIC HYPOTHESlS

Mayer’s [253 influential hypothesis emphasized the importance of glucose metabolism in the control of food intake. He proposed that glucoreceptors in the brain, uniquely sen-

sitive among neurons to the effects of insulin, were respond- ing to decreases in glucose utilization that occur in the postabsorptive state. Decreases in blood glucose were not considered to be the significant variable because animals with diabetes meliitus were known to be hyperphagic despite pronounced hyperglycemia.

Some years after these ideas were first proposed, a decrease in glucose utilization produced by the systemic administration of 2-deoxyglucose (2-DG) was found to increase food intake in rats [35]. The importance of the brain in de- tecting the change in glucose metabolism was demonstrated by findings that eating also was elicited when 2-DG was administered intracerebrovent~cul~Iy 1281. Moreover, sugars that could compete with 2-DG for entrance into brain cells, such as glucose and mannose, when coinfused with 2-DG were found to block its effect on food intake. In contrast, fructose, which cannot cross the blood-brain barrier and thus cannot compete with 2-DG for entry into brain cells, had no effect on food intake despite the fact that it could compete with 2-DG for entrance into all peripheral cells (421. These and other experiments [34] suggested to us that acute glucoprivation in the brain was providing the signal to eat after systemic 2-DC treatment.

Pharmacological doses of insulin also are known to increase food intake 130,371, presumably owing to the decrease in glucose utilization that occurs in certain brain cells secon- dary to the decrease in blood glucose. Not only do animals eat after insulin-induced hypoglycemia, they also increase their mobilization of glucose and other metabolic fuels from stores in an apparent effort to maintain caloric homeostasis. Flatt et d. [IO] had shown that these physiological counter- regulatory responses were not controlled simply by activity at a central glucoreceptor because administ~tion of ketone bodies, which could be utilized by brain cells, eliminated

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688 STRICKER AND McCANN

those responses despite continued hypoglycemia. We won- dered whether the same receptor system also was involved in the elicitation of food intake. Accordingly, we infused various nutrients into hypoglycemic rats and studied their effects on circulating catecholamines (a reflection of activity in the sympathoadren~ system) and on food intake [31,43]. We found, as expected, that the administration of mannose or beta-hydroxybutyrate decreased catecholamine levels back to normal whereas fructose did not. We also observed that mannose and beta-hydroxybutyrate decreased food intake, suggesting that the cerebral receptor was a chemoreceptor, not a glucoreceptor. However, we were surprised to find that fructose also decreased eating induced by large doses of insulin, despite blood glucose levels of 40-50 mg/dl. This suggested that fructose had some peripheral site of action, which inhibited the hunger-inducing effects of insulin-induced cerebral glucoprivation. Later work by Granneman and Friedman [12,13] indicating that hepatic vagotomy abolished this satiating effect of fructose suggested that the liver was the site of the satiety signal.

To summarize, these findings indicate that cerebral glucoprivation, detected by a central chemoreceptor, could elicit feeding in rats. Severe hypoglycemia is an unusual situation, of course, and thus the elicited feeding might be viewed as an “emergency response,” reminiscent of the sympathetic response resulting from cerebral ischemia that is’ not otherwise involved in the control of arterial blood pressure. Although studies of feeding during glucoprivation are consistent with the glucostatic hypothesis, that hypothesis was meant to address normal eating, not eating in response to unusual emergencies. To deal with normal eating, we have preserved the gist of the glucostatic hypothesis and simply mod~ed where the critical event was to occur; that is, we propose that hunger begins when glucose utilization decreases and the mobilization of metabolic fuels begins in the postabsorptive period, owing to some signal generated in the periphery [14]. From the above results, we supposed that the critical signal came from the liver and reflected a decreased delivery of utilizable metablic fuels. To the extent that a decrease in insulin levels is important for hepatic glucose production, then insulin can be thought to participate in the postprandial satiating effects of food [38].

There are two implications of this perspective to be noted. First, when large doses of insulin are administered to experimental animals, the initial increase in glucose utilization resembles the normal physiological effects of food and insulin during the postp~dial period and, consequently, satiety might be expected then, not hunger. In fact, there is an initial period of satiety after insulin administration and the onset of hunger occurs later [17,24], when cerebral glucoprivation becomes so severe that a sympathoadrenal response is elicited, thus causing the mobilization of metabolic fuels despite marked hype~su~ism. In this regard, we have found that blunting the sympathetic response by bilateral adrenal enucleation eliminates the increase in food intake despite blood sugar levels of 40-50 mg/ml[71. Such hypoglycemia would not interfere with eating in intact rats.

The second implication of this perspective is that in the diabetic animal, hyperphagia results from the loss of the satiating effects of food rather than from cerebral glucoprivation [ 111. We examined this hypothesis in rats with varying levels of streptozotocin-induced damage to the pancreas [22]. Animals with relatively little glucose intolerance were found to eat normally, presumably because enough insulin remained to permit normal disposal of caloric loads from

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GLUCOSE CONC. (%I

FIG. 1. Gastric emptying rate after 3 ml loads of glucose solution were administered to rats, as a functon of glucose concentration. Some rats were oretreated with insulin (3 U/kg, SC). Gastric con- tents were monitored at S-10 min intervals for up to & min (n==S-10 animals per time point) and the rates of emptying were found to be linear after an initial bolus. Symbols represent those steady-state rates, computed by least mean squares analysis. From McCann and Stricker [26].

normal-sized meals. However, when those animals were de- prived of food overnight and then permitted to eat freely during the next day, we found that they increased their food consumption and that individual intakes were proportional to the induced glucose intolerance. The increased eating took the form of shorter intermeal intervals rather than bigger meals; that is, the initial postfast meal did not remain satiating for a normal amount of time. These results are consistent with the hypothesis that insulin contributes importantly to the satiating effects of food.

GASTRIC EMPTYING

Modem speculations about the control of food intake began with the influential work of Cannon early in this cen- tury, relating food intake to gastric fill [6]. Although such notions were largely ignored while scientists were preoccu- pied with studies of the central controls of food intake, there has been a recent revival of interest in the stomach and intestines, in large part due to the work of McHugh and his colleagues 1271. They found that there was a well-regulated movement of calories from the stomach to the intestines in monkeys, such that gastric emptying was constant regardless of the nature and density of the caloric load. Moreover, they found that delivery of calories to the intestines slowed gastric emptying and, because gastric distention was prolonged, animals decreased their food intake to compensate for the administered calories. Thus, the stomach could be imagined as an active participant in the regulation of catoric homeostasis, and was not simply a repository of the ingested food.

For the past few years we have used this perspective as a basis for studies of food intake by rats. We find that after an

VISCERAL FACTORS CONTROL FOOD INTAKE 689

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GLUCOSE CONC (%) FIG. 2. Gastric emptying rate of 3 ml loads of varying glucose concentration. Values for control animals were recalculated from data presented in Fig. 1. The other rats had been made diabetic 2-3 weeks earlier by streptozotocin treatment, but then were treated identically as the control animals.

initial bolus, gastric loads of glucose solutions empty at a relatively constant rate of caloric delivery, as in monkeys. However, in rats this rate appeared to depend upon the concentration of the load, with more concentrated solutions emptying much more rapidly than dilute solutions (in calimin; Fig. I). Although dilute glucose solutions left the stomach much more rapidly than concentrated solutions did (in mlimin; Fig. 2), this high rate evidently did not compensate for the reduced caloric density of the loads.

In considering these findings, we imagined that loads of the dilute glucose solutions emptied rapidly, like nonnutrient liquids such as water or saline, because the animals could not detect their caloric content readily. Inadequate stimulation of putative visceral glucoreceptors might be at fault: that is, gastric loads of the more concentrated glucose solutions might provoke enough of a parasympathetic reflex to some- how establish caloric delivery at 30-4.5 calimin, the basal metabolic rate of rats (201, whereas loads of the dilute solutions might not. In other words, the differential parasympathetic reflexes after the various glucose loads might permit concentrated solutions to be emptied more rapidly (in Cal/mitt) than dilute solutions.

Other experiments are consistent with this hypothesis. For example, pharmacological doses of insulin produced a marked increase in gastric emptying of glucose loads, to 30-45 cal/min, that was independent of glucose concentration (Fig. 1). This was most clear when the gastric loads contained the more dilute glucose solutions, because then the basal rates of emptying were very slow. We presume that a central signaf, perhaps resulting from cerebral glucoprivation, initiated the increased vagal activity to the stomach that resulted in increased gastric emptying. These findings allow the hypothesis that when pharmacological doses of insulin are used to elicit food intake, the parallel increase in gastric emptying shortens the duration of gastric distention, thereby decreasing the postprandial satiety period and increasing meal frequency.

Additional insights into the control of gastric emptying

FIG. 3. Schematic representation of some of the physiologic~ factors that appear to be involved in the control of food intake. Thick arrows represent the flow of calories after food ingestion; thin arrows represent excitatory and inhibitory effects of peripheral changes, including the taste of food, on central control mechanisms. From Stricker [391.

and its possible relation to food intake came from studies of rats with streptozotocin-induced diabetes. In these animals there is a chronic mobilization of calories from liver and adipose tissue resulting from the hypoinsulinism, not unlike the au- tonomic response to acute hypoglycemia; as well, the diabetic rats emptied glucose solution much more rapidly than did intact rats (in mllmin; Fig. 2f, at constant rates of 30-4 calimin that were identical to those seen in rats with insulin- induced hypoglycemia. These observations suggest that there was an increased vagal activity to the stomachs of the diabetic animals, which served to increase gastric emptying (see also [16]). The findings also suggest that diabetic hyperphagia might be associated with the decreased duration of satiety signals from the stomach (due to rapid gastric emptying of food) coupled with a loss of postabsorptive satiety signals.

Note that gastric emptying of 520% glucose solutions after insulin treatment was 35-45 cal/min. This rate is not maximal: the gastric emptying of 20% glucose by hypoglycemic rats was only one-fourth that of 20% xylose, an equiosmotic solution that would not be expected to generate a postabsorptive satiety signal. These findings suggest that the postabsorptive delivery of glucose to some site is important for generating a signal limiting gastric emptying to 30-45 cal/min. That site appears to be in the periphery, because infusion of fructose eliminated the effect of insulin-induced hypoglycemia on the gastric emptying of 5% glucose solution. More specific attention to the liver is suggested by additional findings that hepatic vagotomy abolished that effect of infused fructose.

To summarize, we have been using the following schematic arrangement of the various influences on food intake that were mentioned above (Fig. 3; [39]). Our model contains two satiety signals, one related to gastric distention and one related to the delivery of utilizable calories to the

690 STRICKER AND MCCANN

liver. We imagine that when eating, increasing gastric fill and increasing hepatic delivery of calories both serve to reduce the likelihood that animals will continue to feed. Once they stop eating, we suppose that they will remain satiated despite an empty stomach so long as the liver continues to get utilizable calories from the intestines. At some point during the postabsorptive state, however, when satiety signals from the liver and stomach are absent, the animal may be expected to eat again. G

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IMPLICATIONS

There are three issues relating to this perspective that we want to consider briefly.

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1. Because calories are absorbed rapidly from the intestines, gastric emptying and delivery of calories to the liver should be closely correlated events. Thus, removal of the putative satiety signal from the liver by haptic vagotomy should not have much effect on meal frequency under normal circumstances because the remaining signal to the brain from the stomach still could be responsible for controlling food intake. Perhaps for that reason, several studies have failed to find an effect of hepatic vagotomy on ad lib food intake ([3,23] but also see [33]). On the other hand, as mentioned previously, during the contrived conditions in which hypoglycemia was induced by pharmacological doses of insulin but food intake was suppressed by intravenous infusion of fructose, hepatic vagotomy was found to remove that inhibition and permit feeding to occur again [ 121. Simi- larly, when food was restored to rats after overnight deprivation, the first meal that they ingested was an unusual- ly large one and intact rats then showed a prolonged period of satiety, as might be expected; in contrast, our recent observations indicate that hepatic vagotomized animals soon re- turned to eat (Fig. 4), presumably because the liver could not provide postabsorptive satiety signals or inhibition of gastric emptying in this situation. As discussed above, comparable findings were obtained in rats with an intact vagus but an impaired capacity to secrete insulin and thereby store glyco- gen in liver [22].

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TIME (hr) FIG. 4. Intake of Purina Chow pellets by rats after 21 hr food deprivation. Values shown are meansrSE, measured every 2 hr, for 7 control animals and 6 hepatic vagotomized (vagox) rats. After in- gesting comparable amounts during the first 4 hr of the test, vagox animals continued to feed whereas control rats did not (p<O.OOl).

2. This presentation has focused on controls of gastric emptying as they affect individual meals. However, the long-term controls of food intake involving the maintenance of a stable body weight could be integrated with the present views if one assumed that adipose tissue influenced food intake indirectly, by influencing gastric emptying and/or the putative message from the liver to the brain. Thus, for example, the period of hyperphagia that occurs after enforced starvation may be associated with an acceleration in gastric emptying, which would permit food to rush through the gastrointestinal tract en route to the depleted adipocytes. We have just begun to test this proposal, but it is noteworthy in this regard that Booth [4] has reported recently that there is a marked acceleration of gastric emptying in rats after lesions of the ventromedial hypothalamus, which also is known to increase the storage of metabolic fuels in association with increased food intake.

“regress” to an earlier stage of recovery characterized by akinesia and catalepsy [40]. The same observations have been made when rats with LH lesions are given a neurolep- tic, thus implicating the dopaminergic neurons of the brain in this dysfunction. It is by now well-recognized that LH lesions interrupt dopaminergic neurons as they ascend to the forebrain from the substantia nigra [48] and recently we have found that rats with large DA-depleting brain lesions without hypothalamic damage also do not eat in response to 2-DG treatment but show increased akinesia and catalepsy [36,46].

3. Lateral hypothalamic (LH) lesions are well known to produce an initial period of aphagia and anorexia, although ultimately animals often recover more normal feeding behavior [47]. Rats that resume eating and drinking readily after bilateral LH lesions nevertheless do not increase food intake after systemic administration of insulin or 2-DG [9, 41, 491. In considering why the brain-damaged animals do not eat, it is instructive to note that after acute glucoprivation animals

The effects on gastric emptying of the lesions and the 2-DG treatment remain to be determined. However, we have begun to evaluate the effects of 2-DG on the activity of central DA neurons. Two possibilities have been considered. First, 2-DG may cause such a large increase in DA release that residual dopaminergic neurons in the brain-damaged animal cannot sustain DA synthesis and therefore exhaust their supply of transmitter. Using in vivo voltammetry to assess DA release in the intact unanesthetized rat, however, we could find no evidence that 2-DG augments DA release at all, much less produces a huge increase [18]. Alternatively, we considered the possibility that 2-DG interferes with metabolic processes in the dopaminergic neurons that remain after subtotal brain damage, so that DA synthesis in the hyperactive cells is impaired. Using in vitro studies of striatal tissue slices, and measuring DA release by electrical field stimulation, we find that DA release is markedly reduced by 2-DG treatment. Although such work is still in progress, our orientation is that 2-DG decreases food intake in brain-

VISCERAL FACTORS CONTROL FOOD INTAKE 691

damaged rats, in part, because it compromises the function of the residual dopaminergic neurons whose activity is so vital to behavior [45].

SUMMARY AND CONCLUSIONS

The daily food consumption may be computed as the product of the average meal size times the number of meals each day. If meal size is relatively constant, then daily food intake simply reflects either the number of such meals or the intervals between meals. LeMagnen [21] has shown that the intermeal intervals should be viewed as periods of diminish- ing postprandial satiety. Accordingly, we have oriented our discussion around two factors that we believe may provide important signals of satiety, gastric distention and the postabsorptive delivery of utilizable calories to the liver. These factors are not independent of one another; we have seen that events in the liver can influence gastric emptying, and it is not unlikely that eating can affect hepatic function prior to food absorption. The role of the brain in integrating

these messages in the control of food intake remains unclear. The hypothesis of dual hypothalamic centers that control food intake is no longer assumed to be a useful model of brain function, but aside from the demonstrated significance of central dopaminergic neurons to eating and other volun- tary behaviors, central systems that are involved in the control of food intake have not yet been determined. It is evident that further research is needed to identify such systems and to determine how their activity is influenced by signals from the periphery and integrated with the physiological contri- butions to caloric homeostasis.

ACKNOWLEDGEMENTS

This research was supported, in part, by grants MH-25140 and MH-29670. and by Research Scientist Award MH-00338, from the United States National Institute of Mental Health. We are grateful to Jen-shew Yen for her expert technical assistance, and to Dr. Mauricio Russek for his helpful comments regarding this review.

1. Anand, B. K. and J. R. Brobeck. Localization of a “feeding center” in the hypothalamus of the rat. Prcx Sot Exp Biol Mrd 77: 323-324, 1951.

2. Antin, J., J. Gibbs, J. Holt, R. C. Young and G. P. Smith. Cholecystokinin elicits the complete behavioral sequence of satiety in rats. ./ Camp fhysiol Psycho/ 89: 784-790, 1975.

3. Bellinger, L. L., V. E. Mendel, F. E. Williams and T. W. Cas- tonguay. The effect of liver denervation on meal patterns, body weight and body composition of rats. Physiol Behnv 33: 661- 667, 1984.

4. Booth, D. A. Rapid gastric emptying: A nonendocrine au- tonomic mechanism in VMH obesity. Poster presented at the Eighth International Conference on the Physiology of Food and Fluid Intake. Melbourne, Australia, August 1983.

5. Brobeck, J. R., J. Tepperman and C. N. H. Long. Expe~mental hypoth~amic hype~hagia in the albino rat. Yule J Biot Med 15: 831-853, 1943.

6. Cannon, W. B. and A. L. Washburn. An explanation of hunger. Am 3 Physioi 29: 441-454, 1912.

7. Cobum, P. C. and E. M. Stricker. Physiological and behavioral counter-regulatory responses to insulin-induced hypoglycemia. Sot Neurosci Abstr 7: 653, 1981.

8. Davis, J. D., C. S. Campbell, R. J. Gallagher and M. A. Zurakov. Disappearance of a humoral satiety factor during food deprivation. 3 Camp Physiul PsychoI 75: 476-482, 1971.

9. Epstein, A. N. and P. Teitelbaum. Specific loss of the hypoglycemic control of feeding in recovered lateral rats. Am J Ph_ysiol 213: 1159-1167, 1967.

10. Flatt, J. P., G. L. Blackbum, G. Randers and J. B. Stanbury. Effects of ketone body infusion on hypoglycemic reaction in postabsorptive dogs. ~e~~b~~i~~ 23: 151-158, 1974.

11. Friedman, M. I. Hype~hagia in rats with experimental diabetes mellitus: A response to a decreased supply of utilizable fuels. J Ct~rnp Physiol Psycho1 92: lOQ- 117, 1978.

12. Friedman, M. I. Hepatic-cerebral interactions in insuiin- induced eating and gastric acid secretion. Brain Res Bull 5: fh~ooi 4. 63-68. 1980.

13. Friedman, M. I. and J. G. Granneman. Food intake and peripheral factors after recovery from insulin-induced hypoglycemia. Am 3 Phvsiol 244: R374-R382. 1983.

14. Friedman, M. 1. and E. M. Stricker. The physiological psychology of hunger: A physiological perspective. Psycho1 Rev 83: 409-131, 1976.

15. Gibbs, J., R. C. Young and G. P. Smith. Cholecystokinin decreases food intake in rats. J Cnmp Physictt Ps,vchctl84: 488-495, 1973.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

Granneman, J. G. and E. M. Stricker. Food intake and gastric emptying in rats with streptozotocin-induced diabetes. Am 3 Ph,ysiol. 247: R1054-R1061, 1984. Janowitz, H. D. and A. C. Ivy. Role of blood sugar levels in spontaneous and insulin-induced hunger in man. J Appl Physiol I: 643-645, 1949. Keller, R. W., Jr., E. M. Stricker and M. J. Zigmond. Environ- mental stimuli but not homeostatic challenges produce apparent increases in dopaminergic activity in the striatum: An analysis by in vivo voltammetry. Brain Res 279: 159-170, 1983. Kennedy, G. C. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Sot Len (Biol) 40: 578-592, 1953. LeMagnen, J. and M. Devos. Metabolic correlates of the meal onset in the free food intake of rats. Physiol Brhav 5: 805-814, 1970. LeMagnen, J. and M. Devos. Parameters of the meal pattern in rats: Their assessment and physiological significance. Neurosci Biobehav Rev 4: 1-I 1, 1980. Lindberg, N. O., P. C. Cobum and E. M. Stricker. Increased feeding by rats after subdiabetogenic steptozotocin treatment: A role for insulin in satiety. Behuv Neurosci 98: 138-145, 1984. Louis-Sylvestre, J., J. M. Servant, R. Molimard and J. LeMag- nen. Effect of liver denervation on the feeding pattern of rats. Am 3 Physiol 239: Rf&R70, 1980. Lovett, D. and D. A. Booth. Four effects of exogenous insulin on food intake. Q J Exp Psycho/ 22: 406419, 1970. Mayer, J. Regulation of energy intake and the body weight: The glucostatic theory and the lipostatic hypothesis. Ann NY Atad Sri 63: 15-42, 1955. McCann, M. J. and E. M. Stricker. Increased gastric emptying parallels increased food intake in rats. Sot Nfurosci Absfr 9: 201, 1983. McHugh, P. R. Aspects of the control of feeding: Application of quantitation in psychobiology. 3ohns Napkins Med 3 144: 147- 155, 1979. Miselis, R. R. and A. N. Epstein. Feeding induced by intracere- broventricular 2-deoxy-D-glucose in the rat. Am 3 Physiol 29: 1438-1447, 1975. Powley, T. L. The ventromedial hypothalamic syndrome, satiety. and a cephalic phase hypothesis. Psycho1 Rev 84: 89-126, 1977. Richter, C. P. increased dextrose appetite of normal rats treated with insulin. Am J Physi~ll 135: 781-787, 1942. Rowland, N. and E. M. Stricker. Differential effects of glucose and fructose infusions on insulin-induced feeding in rats. Phwioi Behat, 22: 387-389, 1979.

692 STRICKER AND MCCANN

32. Russek, M. Participation of hepatic ghrcoreceptors in the control of intake of food. Nature 197: 79-80, 1963.

33. Russek, M. Reply to commentary on “Current status of the hepatostatic theory of food intake control.” Appetite 2: 157- 162, 1981.

34. Russell, P. J. D. and G. J. Mogenson. Drinking and feeding induced by jugular and portal infusions of 2-deoxy-D-glucose. Am J Physiol 229: 1014-1018, 1975.

35. Smith, G. P. and A. N. Epstein. Increased feeding in response to reduced glucose utilization in the rat and monkey. Am J Physiol 217: 1083-1087, 1%9.

36. Snyder, A. M., M. J. Zigmond and E. M. Stricker. Stress- induced neurological impairments in an animal model of Parkin- sonism. Ann Neural, in press.

37. Steffens, A. B. The influence of insulin injections and infusions on eating and blood glucose level in the rat. Physiol Behav 4: 823-828, 1%9.

38. Stricker, E. M. The central control of food intake: A role for insulin. In: The Neural Basis of Feeding and Reward, edited by B. G. Hoebel and D. Novin. Brunswick, ME: Haer Institute, 1982, pp. 227-240.

39. Snicker, E. M. Biological bases of hunger and satiety:

40

41

Therapeutic implications: Nurr Rels 42: 333-340, 1984. Stricker, E. M., P. H. Cooper, J. F. Marshall and M. J. Zig- mond. Acute homeostatic imbalances reinstate sensorimotor dysfunctions in rats with lateral hypothalamic lesions. J Camp Physiol Psycho1 93: 512-521, 1979. Stricker, E. M., M. I. Friedman and M. J. Zigmond. Glucoregulatory feeding by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions. Science 189: 895-897, 1975.

42.

43.

44.

45.

46.

47.

48.

49.

Stricker, E. M. and N. Rowland. Hepatic versus cerebral origin of stimulus for feeding induced by 2-deoxy-D-glucose in rats. .I Cotnp Physiol Psycho1 92: 126132, 1978. Stricker, E. M., N. Rowland, C. F. SaUer and M. I. Friedman. Homeostasis during hypoglycemia: Central control of adrenal secretion and peripheral control of feeding. Scirncc 196: 79-81. 1977. Stricker, E. M. and M. J. Zigmond. Recovery of function after damage to central catecholamine-containing neurons: A neuro- chemical model for the lateral hypothalamic syndrome. In: Progress in Psychbiology and Physiological Psychology, vol 6, edited by J. M. Sprague and A. N. Epstein. New York: Aca- demic Press, 1976, pp. 121-188. Stricker, E. M. and M. J. Zigmond. Brain monoamines, homeostasis, and adaptive behavior. In: Handbook of Physiology, edited by F. E. Bloom. Bethesda. MD: American Physiological Society, 1985, in press. Snicker, E. M., M. B. Zimmerman, M. I. Friedman and M. J. Zigmond. Caffeine restores feeding response to 2- deoxy-D-glucose in 6-hydroxydopamine-treated rats. Nature 267: 174-175, 1977. Teitelbaum, P. and A. N. Epstein. The lateral hypothalamic syndrome: Recovery of feeding and drinking after lateral hypothalamic lesions. Psycho/ Rev 69: 75-90, 1%2. Ungerstedt, U. Aphagia and adipsia after 6hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acru Physiol Scund Suppl 367: 95-122, 1971. Wayner, M. J., A. Cott, J. Millner and R. Tartaghone. Loss of 2-deoxy-D-glucose induced eating in recovered lateral rats. Physiol Behav 7: 881-884, 1971.

visceral factors in the control of food intake

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