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Glucoregulatory feeding in cats
Physiology & Behavior, Vol. 26, pp. 901-903. Pergamon Press and Brain Research Publ., 1981. Printed in the U.S.A.
Glucoregulatory Feeding in Cats NEIL ROWLAND
Departments of Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA 15260 R e c e i v e d 29 August 1980 ROWLAND, N. Glucoregulatoryfeeding in cats. PHYSIOL. BEHAV. 26(5) 901-903, 1981 .--A fourfold increase in food intake was observed after IP injections of 2-deoxy-D-glucose (50 and 100 mg/kg) in domestic cats. A dose of 200 mg/kg was less effective, and the animals appeared sick. Cats also increased food intake after insulin injection and food deprivation, indicating that they have glucoprivic and short term controls of feeding similar to rats and many other mammals.
2-deoxy-D-glucose
Insulin
Glucoprivation
Cat
THE COMPETITIVE blockade of intracellular glycolysis by 2-deoxy-D-glucose (2DG) elicits compensatory behavioral and physiological responses in most mammals [2, 3, 8, 9, 10, 17, 19]. Notable exceptions are cats and hamsters, both of which exhibit the physiological responses (hyperglycemia was the most usual index) but apparently do not increase their food intake after injections of 2DG [4, 11, 12, 13, 15]. Golden hamsters show a remarkable inflexibility in their meal patterns under a number of conditions such as imposed feeding schedules [1,16], and their failure to eat after 2DG may be related to this inflexibility. However, cats do exhibit flexible meal patterns [6], and their failure to eat after 2DG [4] is thus of considerable interest. Jalowiec et al. [4] reported that IP injections of 2DG in doses of 250-750 mg/kg suppressed feeding in undeprived cats. Such decreased food intake might reflect, for example, some nonspecific stressful aspects of the IP injection rather than the absence of a glucoprivic feeding mechanism. In a pilot study, one cat was implanted with an indwelling jugular vein catheter in order to give smaller, non-painful injections. In one test, 50 mg/kg 2DG elicited an immediate feeding response, but infections then developed and subsequent tests were not possible. This result suggested that under appropriate conditions cats might exhibit 2DG-elicited feeding, and the following experiments were performed.
Food intake
shelf, food and water dishes. The cats were serviced regularly and received Purina cat chow ad lib, along with tap water. The colony room was ventilated, maintained at 220C, with a natural day-night cycle. All feeding tests started between 1000-1100 hr, and food dishes were weighed initially (_+0.1 g), and after 1, 2 and 3 hr, correcting for any spillage. Baseline feeding tests were immediately preceded by injection of 0.9% NaCI (0.5 mi/kg, IP) or no injection; the food intakes were similar in both cases. At least one baseline test was run between each experimental treatment, and a total of six baseline test intakes were averaged to form a mean for each cat. On experimental days, 2DG (Sigma) was injected IP in 0.5 ml/kg 0.9% NaCI carrier. The order of treatments was the same for each cat: 50, I00, 100, 50, and 200 mg/kg 2DG, and each drug day was separated by 2-3 no-drug days the last of which was a baseline test. The data for replicate doses were similar, and an average has been used in the analysis. The cats were held gently by their usual handler for IP injections, and appeared undisturbed by the procedure. The cats maintained body weight and were in excellent health throughout the experiment. One additional test, performed after the 213(3 experiments, involved measuring the hourly food intake for 3 hr after 24 hr food deprivation. RESULTS
METHOD
Three adult male domestic cats weighing 2.6-4.8 kg participated in this study. These cats were selected for their docile disposition which would be likely to minimize any distress during the injection procedures. They had lived in the laboratory for several years and, at least 1 year prior to this work, some had been trained in a shock-motivated avoidance task. Two of the cats had also been used in a 2 hr/day walking exercise study some 3 months prior to the present work. The cats were housed individually in 45x60x65 cm stainless steel cages (Hoeltge) equipped with a litter box,
Figure 1 shows that all three cats exhibited large increases in food intake following 50 and 100 mg/kg 2DG. Most of the elicited feeding occurred in the first and second hours after the injection and, over the 3 hr period, the increases were up to 400% above baseline. Little or no feeding occurred after the third hour. In contrast to the large and reliable increases in food intake after 50 and 100 mg/kg 2DG, the effects of 200 mg/kg were less robust. Cats 1 and 2 started to eat within 15 rain of the injection, but then vomited and did not eat for the remainder of the test period (and remained hypophagic for the
1This research was supported by grant AM 26231 from NIH. I am grateful to Dr. Francis Colavita for access to his cat colony, and to Donna Kocan for taking care of the animals. Send reprint requests to Neff Rowland, Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260.
Copyright © 1981 Brain R e s e a r c h Publications Inc.--0031-9384/81/050901-03502.00/0
902
ROWLAND
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hours lillinjettion FIG. 1. Food intake (grams of cat chow) of individual cats at hourly intervals after injection of 50, 100 or 200 mg/kg 2-deoxy-D-glucose. Baseline (B) measures were obtained after no injection or isotonic saline, and are the average of six determinations. The intakes after 50 and 100 mg/kg are averages of two determinations, except for cat no. 1 at 100 mg/kg. Also shown are the cumulative intakes following 24 hr food deprivation (DEP).
next day). Indeed, cat 1 experienced emesis within 30 min of its second treatment with 100 mg/kg 2DG, ate no more during that session, and data from that test are not included in Fig. 1. A Friedman two-way analysis of variance [14] performed on the 3 hr food intakes shown in Fig. 1 for baseline and all three doses of 2DG, revealed that the intakes differed reliably as a function of dose of 2DG (Xr2=7.4, p =0.033). Since the cats were unduly distressed by 200 mg/kg 2DG, we did not examine higher doses. In a subsequent control experiment, no cat vomited after injection of 200 mg/kg D-glucose, indicating that osmolarity cannot account for the sickness. All of the cats increased their food intake above baseline following food deprivation (Fig. 1), and the 3 hr increases were comparable to the effects of the lower doses of 2DG. DISCUSSION The present results indicate that cats have an excellent glucoprivic control of feeding. They ate during cytoglucopenia following administration of moderate doses of 2DG. However, at a higher dose the feeding was apparently
inhibited by sickness, and this may account for a previous report of decreased food intake in cats after still higher doses of 2DG [4]. Humans report hunger after low doses of 2DG, but also experience side effects of general sympathetic arousal including sweating, tachycardia and drowsiness [7, 18, 19]. Such symptoms might well lead to a nonspecific disruption of appetite. Further, as expected from the demonstration that cats are able to modify their feeding patterns with varying availability of food [6], we found increased food intake in the first 3 hr after food deprivation. In these respects, then, cats appear to have glucoprivic and short-term controls of feeding similar to those described in rats and many other mammals. This conclusion is further supported by a subsequent experiment in which two of the cats increased their food intake by 500% above baseline in the 3 hr after injection of regular insulin (0.8 U/kg SC). Cats differ from rats in their failure to compensate for dietary dilution, a finding which can be rationalised by consideration of their carnivorous ancestry [6]. The finding that gerbils increase food intake after deprivation, but not 2DG [12], has not yet been adequately explained.
G L U C O R E G U L A T O R Y F E E D I N G IN CATS
903
REFERENCES 1. Borer, K. T., N. Rowland, A. Mirow, R. C. Borer, Jr. and R. P. Kelch. Physiological and behavioral response to starvation in the golden hamster. Am. J. Physiol. 236: EI05-E112, 1979. 2. Houpt, T. R. Stimulation of food intake in ruminants by 2-deoxyD-glucose and insulin. Am. J. Physiol. 227: 161-167, 1974. 3. Houpt, 1". R. and H. E. Hance. Stimulation of food intake on rabbit and rat by inhibition of glucose metabolism with 2-deoxy-D-glucose. J. comp. physiol. Psychol. 76: 395-400, 1971. 4. Jalowiec, J. E., J. Panksepp, H. Shabshelowitz, A. J. Zolovick, W. Stern and P. J. Morgane. Suppression of feeding in cats following 2-deoxy-D-glucose. Physiol. Behav. 10: 805-807, 1973. 5. Kadekaro, M., C. Timo-Iaria and M. de L. M. Vincentini. Gastric secretion provoked by functional cytoglucopenia in the nuclei of the solitary tract in the cat. J. Physiol. 299: 397-407, 1980. 6. Kanarek, R. B. Availability and caloric density of the diet as determinants of meal patterns in cats. Physiol. Behav. 15:611618, 1975. 7. Landau, B. R., J. Laszlo, J. Stengle and D. Burk. Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-D-glucose. J. natn. Cancer Inst. 21: 485494, 1958. 8. Likuski, H.J., A. F. Debons and R. J. Cloutier. Inhibition of gold thioglucose-induced hypothalamic obesity by glucose analogues. Am. J. Physiol. 212: 669-676, 1967. 9. Novin, D., D. A. VanderWeele and M. Rezek. Infusion of 2-deoxy-D-glucose into the hepatic portal system causes eating: Evidence for peripheral glucoreceptors. Science 181: 858-860, 1973.
10. Parrott, R. F. and B. A. Baldwin. Effects of intracerebroventricular injections of 2-deoxy-D-glucose, D-glucose, and xylose on operant feeding in pigs. Physiol. Behav. 21: 329-331, 1978. 11. Ritter, R. C. and O. K. Balch. Feeding in response to insulin but not to 2-deoxy-D-glucose in the hamster. Am. J. Physiol. 234: E20-E24, 1978. 12. Rowland, N. Effects of insulin and 2-deoxy-D-glucose on feeding in hamsters and gerbils. Physiol. Behav. 21: 291-294, 1978. 13. Sclafani, A. and D. Eisenstadt. 2-deoxy-D-glucose fails to induce feeding in hamsters fed a preferred diet. Physiol. Behav. 24: 641-643, 1980. 14. Siegel, S. Nonparametric Statistics for the Behavioral Sciences. New York, McGraw-Hill, 1956. 15. Silverman, H. J. Failure of 2-deoxy-D-glucose to increase feeding in the golden hamster. Physiol. Behav. 21: 859-864, 1978. 16. Silverman, H. J. and I. Zucker. Absence of post-fast food compensation in the golden hamster (Mesocricetus auratus). Physiol. Behav. 17: 271-285, 1976. 17. Smith, G. P. and A. N. Epstein. Increased feeding in response to decreased glucose utilization in the rat and monkey. Am. J. Physiol. 217: 1083-1088, 1969. 18. Thompson, D. A. and R.-G; Campbell. Hunger in humans induced by-2-deoxy-D-glucose: Glucoprivic control of taste preference and food intake. Science 198: 1065-1068, 1977. 19. Welle, S. L., D. A. Thompson, R. G. Campbell and U. Lilavivathana. Increased hunger and thirst during glucoprivation in humans. Physiol. Behav. 25: 397-403, 1980.
Glucoregulatory Feeding in Cats NEIL ROWLAND
Departments of Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA 15260 R e c e i v e d 29 August 1980 ROWLAND, N. Glucoregulatoryfeeding in cats. PHYSIOL. BEHAV. 26(5) 901-903, 1981 .--A fourfold increase in food intake was observed after IP injections of 2-deoxy-D-glucose (50 and 100 mg/kg) in domestic cats. A dose of 200 mg/kg was less effective, and the animals appeared sick. Cats also increased food intake after insulin injection and food deprivation, indicating that they have glucoprivic and short term controls of feeding similar to rats and many other mammals.
2-deoxy-D-glucose
Insulin
Glucoprivation
Cat
THE COMPETITIVE blockade of intracellular glycolysis by 2-deoxy-D-glucose (2DG) elicits compensatory behavioral and physiological responses in most mammals [2, 3, 8, 9, 10, 17, 19]. Notable exceptions are cats and hamsters, both of which exhibit the physiological responses (hyperglycemia was the most usual index) but apparently do not increase their food intake after injections of 2DG [4, 11, 12, 13, 15]. Golden hamsters show a remarkable inflexibility in their meal patterns under a number of conditions such as imposed feeding schedules [1,16], and their failure to eat after 2DG may be related to this inflexibility. However, cats do exhibit flexible meal patterns [6], and their failure to eat after 2DG [4] is thus of considerable interest. Jalowiec et al. [4] reported that IP injections of 2DG in doses of 250-750 mg/kg suppressed feeding in undeprived cats. Such decreased food intake might reflect, for example, some nonspecific stressful aspects of the IP injection rather than the absence of a glucoprivic feeding mechanism. In a pilot study, one cat was implanted with an indwelling jugular vein catheter in order to give smaller, non-painful injections. In one test, 50 mg/kg 2DG elicited an immediate feeding response, but infections then developed and subsequent tests were not possible. This result suggested that under appropriate conditions cats might exhibit 2DG-elicited feeding, and the following experiments were performed.
Food intake
shelf, food and water dishes. The cats were serviced regularly and received Purina cat chow ad lib, along with tap water. The colony room was ventilated, maintained at 220C, with a natural day-night cycle. All feeding tests started between 1000-1100 hr, and food dishes were weighed initially (_+0.1 g), and after 1, 2 and 3 hr, correcting for any spillage. Baseline feeding tests were immediately preceded by injection of 0.9% NaCI (0.5 mi/kg, IP) or no injection; the food intakes were similar in both cases. At least one baseline test was run between each experimental treatment, and a total of six baseline test intakes were averaged to form a mean for each cat. On experimental days, 2DG (Sigma) was injected IP in 0.5 ml/kg 0.9% NaCI carrier. The order of treatments was the same for each cat: 50, I00, 100, 50, and 200 mg/kg 2DG, and each drug day was separated by 2-3 no-drug days the last of which was a baseline test. The data for replicate doses were similar, and an average has been used in the analysis. The cats were held gently by their usual handler for IP injections, and appeared undisturbed by the procedure. The cats maintained body weight and were in excellent health throughout the experiment. One additional test, performed after the 213(3 experiments, involved measuring the hourly food intake for 3 hr after 24 hr food deprivation. RESULTS
METHOD
Three adult male domestic cats weighing 2.6-4.8 kg participated in this study. These cats were selected for their docile disposition which would be likely to minimize any distress during the injection procedures. They had lived in the laboratory for several years and, at least 1 year prior to this work, some had been trained in a shock-motivated avoidance task. Two of the cats had also been used in a 2 hr/day walking exercise study some 3 months prior to the present work. The cats were housed individually in 45x60x65 cm stainless steel cages (Hoeltge) equipped with a litter box,
Figure 1 shows that all three cats exhibited large increases in food intake following 50 and 100 mg/kg 2DG. Most of the elicited feeding occurred in the first and second hours after the injection and, over the 3 hr period, the increases were up to 400% above baseline. Little or no feeding occurred after the third hour. In contrast to the large and reliable increases in food intake after 50 and 100 mg/kg 2DG, the effects of 200 mg/kg were less robust. Cats 1 and 2 started to eat within 15 rain of the injection, but then vomited and did not eat for the remainder of the test period (and remained hypophagic for the
1This research was supported by grant AM 26231 from NIH. I am grateful to Dr. Francis Colavita for access to his cat colony, and to Donna Kocan for taking care of the animals. Send reprint requests to Neff Rowland, Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260.
Copyright © 1981 Brain R e s e a r c h Publications Inc.--0031-9384/81/050901-03502.00/0
902
ROWLAND
L ,,, 26
! I
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L,'( /
• '
,7
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hours lillinjettion FIG. 1. Food intake (grams of cat chow) of individual cats at hourly intervals after injection of 50, 100 or 200 mg/kg 2-deoxy-D-glucose. Baseline (B) measures were obtained after no injection or isotonic saline, and are the average of six determinations. The intakes after 50 and 100 mg/kg are averages of two determinations, except for cat no. 1 at 100 mg/kg. Also shown are the cumulative intakes following 24 hr food deprivation (DEP).
next day). Indeed, cat 1 experienced emesis within 30 min of its second treatment with 100 mg/kg 2DG, ate no more during that session, and data from that test are not included in Fig. 1. A Friedman two-way analysis of variance [14] performed on the 3 hr food intakes shown in Fig. 1 for baseline and all three doses of 2DG, revealed that the intakes differed reliably as a function of dose of 2DG (Xr2=7.4, p =0.033). Since the cats were unduly distressed by 200 mg/kg 2DG, we did not examine higher doses. In a subsequent control experiment, no cat vomited after injection of 200 mg/kg D-glucose, indicating that osmolarity cannot account for the sickness. All of the cats increased their food intake above baseline following food deprivation (Fig. 1), and the 3 hr increases were comparable to the effects of the lower doses of 2DG. DISCUSSION The present results indicate that cats have an excellent glucoprivic control of feeding. They ate during cytoglucopenia following administration of moderate doses of 2DG. However, at a higher dose the feeding was apparently
inhibited by sickness, and this may account for a previous report of decreased food intake in cats after still higher doses of 2DG [4]. Humans report hunger after low doses of 2DG, but also experience side effects of general sympathetic arousal including sweating, tachycardia and drowsiness [7, 18, 19]. Such symptoms might well lead to a nonspecific disruption of appetite. Further, as expected from the demonstration that cats are able to modify their feeding patterns with varying availability of food [6], we found increased food intake in the first 3 hr after food deprivation. In these respects, then, cats appear to have glucoprivic and short-term controls of feeding similar to those described in rats and many other mammals. This conclusion is further supported by a subsequent experiment in which two of the cats increased their food intake by 500% above baseline in the 3 hr after injection of regular insulin (0.8 U/kg SC). Cats differ from rats in their failure to compensate for dietary dilution, a finding which can be rationalised by consideration of their carnivorous ancestry [6]. The finding that gerbils increase food intake after deprivation, but not 2DG [12], has not yet been adequately explained.
G L U C O R E G U L A T O R Y F E E D I N G IN CATS
903
REFERENCES 1. Borer, K. T., N. Rowland, A. Mirow, R. C. Borer, Jr. and R. P. Kelch. Physiological and behavioral response to starvation in the golden hamster. Am. J. Physiol. 236: EI05-E112, 1979. 2. Houpt, T. R. Stimulation of food intake in ruminants by 2-deoxyD-glucose and insulin. Am. J. Physiol. 227: 161-167, 1974. 3. Houpt, 1". R. and H. E. Hance. Stimulation of food intake on rabbit and rat by inhibition of glucose metabolism with 2-deoxy-D-glucose. J. comp. physiol. Psychol. 76: 395-400, 1971. 4. Jalowiec, J. E., J. Panksepp, H. Shabshelowitz, A. J. Zolovick, W. Stern and P. J. Morgane. Suppression of feeding in cats following 2-deoxy-D-glucose. Physiol. Behav. 10: 805-807, 1973. 5. Kadekaro, M., C. Timo-Iaria and M. de L. M. Vincentini. Gastric secretion provoked by functional cytoglucopenia in the nuclei of the solitary tract in the cat. J. Physiol. 299: 397-407, 1980. 6. Kanarek, R. B. Availability and caloric density of the diet as determinants of meal patterns in cats. Physiol. Behav. 15:611618, 1975. 7. Landau, B. R., J. Laszlo, J. Stengle and D. Burk. Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-D-glucose. J. natn. Cancer Inst. 21: 485494, 1958. 8. Likuski, H.J., A. F. Debons and R. J. Cloutier. Inhibition of gold thioglucose-induced hypothalamic obesity by glucose analogues. Am. J. Physiol. 212: 669-676, 1967. 9. Novin, D., D. A. VanderWeele and M. Rezek. Infusion of 2-deoxy-D-glucose into the hepatic portal system causes eating: Evidence for peripheral glucoreceptors. Science 181: 858-860, 1973.
10. Parrott, R. F. and B. A. Baldwin. Effects of intracerebroventricular injections of 2-deoxy-D-glucose, D-glucose, and xylose on operant feeding in pigs. Physiol. Behav. 21: 329-331, 1978. 11. Ritter, R. C. and O. K. Balch. Feeding in response to insulin but not to 2-deoxy-D-glucose in the hamster. Am. J. Physiol. 234: E20-E24, 1978. 12. Rowland, N. Effects of insulin and 2-deoxy-D-glucose on feeding in hamsters and gerbils. Physiol. Behav. 21: 291-294, 1978. 13. Sclafani, A. and D. Eisenstadt. 2-deoxy-D-glucose fails to induce feeding in hamsters fed a preferred diet. Physiol. Behav. 24: 641-643, 1980. 14. Siegel, S. Nonparametric Statistics for the Behavioral Sciences. New York, McGraw-Hill, 1956. 15. Silverman, H. J. Failure of 2-deoxy-D-glucose to increase feeding in the golden hamster. Physiol. Behav. 21: 859-864, 1978. 16. Silverman, H. J. and I. Zucker. Absence of post-fast food compensation in the golden hamster (Mesocricetus auratus). Physiol. Behav. 17: 271-285, 1976. 17. Smith, G. P. and A. N. Epstein. Increased feeding in response to decreased glucose utilization in the rat and monkey. Am. J. Physiol. 217: 1083-1088, 1969. 18. Thompson, D. A. and R.-G; Campbell. Hunger in humans induced by-2-deoxy-D-glucose: Glucoprivic control of taste preference and food intake. Science 198: 1065-1068, 1977. 19. Welle, S. L., D. A. Thompson, R. G. Campbell and U. Lilavivathana. Increased hunger and thirst during glucoprivation in humans. Physiol. Behav. 25: 397-403, 1980.