- Email: [email protected]
Hepatic glucoreceptors do exist but do not control food intake
Appetite 1981,2,146-148
Hepatic Glucoreceptors do Exist but do not Control Food Intake JEANINE LOUIS-SYLVESTRE
Laboratoire de Neurophysiologie Sensorielle et Comportementale, College de France
While tissue metabolism requires continuous supplies of utilizable fuels, nutriments are ingested periodically, Thus, it seems reasonable to assume: (1) that food intake serves to replenish various fuel reserves: nutriments remaining in the gastrointestinal tract, liver glycogen and fat depots; (2) that the internal stimulus to eat is related to the exhaustion of at least one of these stores, According to this rationale, Dr Russek hypothesizes: (1) that food intake is the effector mechanism of a system that regulates carbohydrate stores; (2) that some innervated hepatocytes are the receptors sensitive to a metabolite of the glycolytic chain, providing information to the brain about this carbohydrate store, Several arguments can be raised against this hypothesis. A careful liver denervation does not produce any change in any characteristics of the ad libitum feeding behavior of either dogs (Bellinger, Trietley & Bernardis, 1976) or rats (Louis-Sylvestre, Servant, Molimard & Le Magnen, 1980). This latter study involved an a posteriori control of both vagotomy and sympathectomy. The test used to verify hepatic vagotomy was as follows: a 30-sec infusion of an 1 IIr, glucose solution administered at a rate of 0·5 ml/min in the portal vein of anesthesized normal animals resulted in a 5'2% variation in the heart rate; no change in cardiac frequency was obtained by the same infusion of a 1'8% saline solution; in liver denervated rats, both infusions were ineffective. The fact that this response is eliminated by the denervation proves that the denervation carried out is effective to abolish a response apparently mediated by hepatic glucoreceptors. However, the fact that the meal pattern is unchanged after such a complete denervation also proves that food intake is not mediated by at least the same hepatic glucoreceptors if any, Moreover, a recent study (Le Magnen & Devos, 1980) has shown that the liver glycogen content, determined in free feeding rats at the beginning of nocturnal meals and 60min later, is highly correlated with the cumulative food intake measured from the beginning of the dark period. This finding clearly rules out the possible involvement of a glycogen decrement in meal onset. This result and others which demonstrate the
Requests for reprints should be sent to Jeanine Louis-Sylvestre, Laboratoire de Neurophysiologie Sensorielle et Comportement ale, College de France, 11 Place Marcelin Berthelot, F-75231 Paris Cedex 05, France. 0195--6663/81/020146+03 S02'OO
(' 1981 Academic Press Inc. (London) Limited
HEPATIC GLUCORECEPTORS AND FOOD INTAKE
147
diurnal cycle of liver glycogen content (Fuller & Diller, 1976; Gagliardino, Pessacq, Hernandez & Rebolledo, 1978; Peret, Macaire & Chanez, 1973) are consistent with the view that the liver glycogen is a carbohydrate store, which, in the same way as the fat store, is involved in the day-night feeding periodicity . The idea that the liver might provide the brain with information concerning current fuel availability is suggested by its strategic position: in normal rats, nearly all nutrients must pass through the liver before they reach the general circulation. However, it has been shown that rats with an end to side portacaval shunt exhibit a normal feeding pattern on a semi-synthetic diet (starch-lard-casein) (Servant, Louis-Sylvestre, Molimard & Le Magnen, Note 1). It has been shown recently (Louis-Sylvestre & Le Magnen, 1980) that a slight fall in blood glucose level precedes the start of each meal. This peripheral blood glucose decrease reflects a deficit in the hepatic glucose output, which is not prevented by the glycogen store and does not inhibit the nocturnal meal-to-meal increase in this carbohydrate store. So it seems likely that the fall of the hepatic glucose output results from a deficit in the upstream hepatic glucose input and more precisely from a decrease in the intraportal flow of metabolites from the intestine. The hypothesis is under investigation. There is good evidence for the existence of hepatic metabolic receptors. Sawchenko and Friedman (1979) have recently reviewed the numerous studies showing the possible involvement of these receptors in feeding behavior: few of them are convincing; or the doses used are out of physiological range; or the comparison between peripheral and portal way of injection is lacking. In this regard, it must be recalled that in undisturbed free feeding rats the blood glucose level undergoes only small variations-from - 5% before the meal to + 20% in the immediate postprandial period for the periphery (Louis-Sylvestre & Le Magnen, 1980) and + 50% for the portal blood (Strubbe & Steffens, 1977). As recently shown by Niijima (1980), the infusion of a small amount of glucose (25 mg/ kg) causes no significant difference in the mean firing rate of the adrenal nerve and the pancreatic vagal branch when given by the jugular vein; by contrast, the same infusion ca uses a significant increase in rate of discharges of the pancreatic nerve and a significant decrease in discharge rate of the adrenal nerve when given by the portal route. The reflex inhibition of adrenaline secretion and reflex activation of insulin secretion might be one ofthe regulatory mechanisms of the moment to moment glucose homeostasis. When strongly recruited by large doses of intraportal glucose, this mechanism could induce considerable changes in systemic glucose level which, in turn and as a secondary effect, could act upon central glucoreceptors governing food intake. This could be an explanation for the results of Novin, Sanderson and VanderWeele (1974), Rezek and Novin (1977) and Russek (1970). So it seems that in undisturbed free feeding animals, the hepatic innervation is not essential for the control offood intake. It is probably involved in the rapid corrections which insure a perfect constancy of blood glucose level during the interprandial periods. R EFERENCE NOTE
1. Servant, J. M., Louis-Sylvestre, J., Molimard, R., & Le Magnen, J . Food intake in rats with portacaval anastamosis. 6th International Conference on the Physiology of Food and Fluid Intake. Jouy en Josas (France), 1977.
148
J. LOU IS-SYL V[STRE RI+E RE~CES
Bellinger, L. L., Trietley, G. J., & Bernardis, L. L. Failure of portal glucose and adrenaline infusions or liver denervation to affect food intake in dogs. Physiology and Behavior, 1976, 16,299- 304. Fuller, R. W., & Diller, E. R. Diurn a l variation ofliver glycogen a nd plasma free fatty acids in rats fed ad libitum or single daily meal. Metabolism, 1970,19,226- 229. Gagliardino, J. J., Pessacq , M. T., Hernandez, R. E., & Rebolledo, O. R. Circadian variations in serum glucagon and hepatic glucogen and cyclic AMP concentrations. Journal of EI/(Iocrill%ql' 1978. 78,297- 298. Le Magnen, J ., & Devos, M. Variations of meal to meal li ver glycogen in rats . Neuroscience LInd Biobehavioral Reviews, 1980, 4 (SuppJ. 1),29-32 Louis-Sylvestre, J., Servant, J . M ., Molimard, R. , & Le Magnen, J. Effect of li ve r denerva tion on the feeding pattern of rats. AmeriUlIl JOUf/1a/ of Phl'si%gl', 1980, 239, R66- R70. Louis-Sylvestre, J., & Le Magnen, J. A fall in blood glucose level precedes meal onset in free feeding rats. Neuroscience and Biobehavioral Reviews, 1980,4 (SuppJ. 1), 13-15. Niijima, A. Glucose sensitive afferent nerve fibers in the liver and regulation of blood glucose . Brain Research Bulletin, 1980,5 (Suppl. 4), 1-5. Novin, D., Sanderson, J. D., & Va nderWeele, D. A. The effect of isotonic glucose on eating as a function of feeding condition and infusion site. Phl'si%{/.r ilnd Behavior, 1974, 13, 3-7. PereL J .. Macaire. I., & Chanez, M. Schedule of protein ingestion, nitrogen and energy utilization a nd circadian rhythm of hepatic glycogen, plasma corticosterone and insulin in rats. Journal of Nutrition, 1973, 103, 866-874. Rezek, M., & Novin, D. Hepatic-portal nutrient infusion: effect on feeding in intact vagotomized rabbits. America/l Journal of Phl'sioloql', 1977, 232, E 1 \9- E 130. Sawchenko, P. E. , & Friedman, M . I. Sensory functions of the li ver; a review. American JOll1'llll/ of Phl'sioloqr. 1979, 236. R5- R20 . Strubbe, J. H.,& Steffens, A. B. Blood glucose levels in portal and peripheral circulation and their re lation to food intake in the rat. Phrsi%gy and Behavior, 1977, 19, 303- 307.
R eceived 11 November, 1980
Hepatic Glucoreceptors do Exist but do not Control Food Intake JEANINE LOUIS-SYLVESTRE
Laboratoire de Neurophysiologie Sensorielle et Comportementale, College de France
While tissue metabolism requires continuous supplies of utilizable fuels, nutriments are ingested periodically, Thus, it seems reasonable to assume: (1) that food intake serves to replenish various fuel reserves: nutriments remaining in the gastrointestinal tract, liver glycogen and fat depots; (2) that the internal stimulus to eat is related to the exhaustion of at least one of these stores, According to this rationale, Dr Russek hypothesizes: (1) that food intake is the effector mechanism of a system that regulates carbohydrate stores; (2) that some innervated hepatocytes are the receptors sensitive to a metabolite of the glycolytic chain, providing information to the brain about this carbohydrate store, Several arguments can be raised against this hypothesis. A careful liver denervation does not produce any change in any characteristics of the ad libitum feeding behavior of either dogs (Bellinger, Trietley & Bernardis, 1976) or rats (Louis-Sylvestre, Servant, Molimard & Le Magnen, 1980). This latter study involved an a posteriori control of both vagotomy and sympathectomy. The test used to verify hepatic vagotomy was as follows: a 30-sec infusion of an 1 IIr, glucose solution administered at a rate of 0·5 ml/min in the portal vein of anesthesized normal animals resulted in a 5'2% variation in the heart rate; no change in cardiac frequency was obtained by the same infusion of a 1'8% saline solution; in liver denervated rats, both infusions were ineffective. The fact that this response is eliminated by the denervation proves that the denervation carried out is effective to abolish a response apparently mediated by hepatic glucoreceptors. However, the fact that the meal pattern is unchanged after such a complete denervation also proves that food intake is not mediated by at least the same hepatic glucoreceptors if any, Moreover, a recent study (Le Magnen & Devos, 1980) has shown that the liver glycogen content, determined in free feeding rats at the beginning of nocturnal meals and 60min later, is highly correlated with the cumulative food intake measured from the beginning of the dark period. This finding clearly rules out the possible involvement of a glycogen decrement in meal onset. This result and others which demonstrate the
Requests for reprints should be sent to Jeanine Louis-Sylvestre, Laboratoire de Neurophysiologie Sensorielle et Comportement ale, College de France, 11 Place Marcelin Berthelot, F-75231 Paris Cedex 05, France. 0195--6663/81/020146+03 S02'OO
(' 1981 Academic Press Inc. (London) Limited
HEPATIC GLUCORECEPTORS AND FOOD INTAKE
147
diurnal cycle of liver glycogen content (Fuller & Diller, 1976; Gagliardino, Pessacq, Hernandez & Rebolledo, 1978; Peret, Macaire & Chanez, 1973) are consistent with the view that the liver glycogen is a carbohydrate store, which, in the same way as the fat store, is involved in the day-night feeding periodicity . The idea that the liver might provide the brain with information concerning current fuel availability is suggested by its strategic position: in normal rats, nearly all nutrients must pass through the liver before they reach the general circulation. However, it has been shown that rats with an end to side portacaval shunt exhibit a normal feeding pattern on a semi-synthetic diet (starch-lard-casein) (Servant, Louis-Sylvestre, Molimard & Le Magnen, Note 1). It has been shown recently (Louis-Sylvestre & Le Magnen, 1980) that a slight fall in blood glucose level precedes the start of each meal. This peripheral blood glucose decrease reflects a deficit in the hepatic glucose output, which is not prevented by the glycogen store and does not inhibit the nocturnal meal-to-meal increase in this carbohydrate store. So it seems likely that the fall of the hepatic glucose output results from a deficit in the upstream hepatic glucose input and more precisely from a decrease in the intraportal flow of metabolites from the intestine. The hypothesis is under investigation. There is good evidence for the existence of hepatic metabolic receptors. Sawchenko and Friedman (1979) have recently reviewed the numerous studies showing the possible involvement of these receptors in feeding behavior: few of them are convincing; or the doses used are out of physiological range; or the comparison between peripheral and portal way of injection is lacking. In this regard, it must be recalled that in undisturbed free feeding rats the blood glucose level undergoes only small variations-from - 5% before the meal to + 20% in the immediate postprandial period for the periphery (Louis-Sylvestre & Le Magnen, 1980) and + 50% for the portal blood (Strubbe & Steffens, 1977). As recently shown by Niijima (1980), the infusion of a small amount of glucose (25 mg/ kg) causes no significant difference in the mean firing rate of the adrenal nerve and the pancreatic vagal branch when given by the jugular vein; by contrast, the same infusion ca uses a significant increase in rate of discharges of the pancreatic nerve and a significant decrease in discharge rate of the adrenal nerve when given by the portal route. The reflex inhibition of adrenaline secretion and reflex activation of insulin secretion might be one ofthe regulatory mechanisms of the moment to moment glucose homeostasis. When strongly recruited by large doses of intraportal glucose, this mechanism could induce considerable changes in systemic glucose level which, in turn and as a secondary effect, could act upon central glucoreceptors governing food intake. This could be an explanation for the results of Novin, Sanderson and VanderWeele (1974), Rezek and Novin (1977) and Russek (1970). So it seems that in undisturbed free feeding animals, the hepatic innervation is not essential for the control offood intake. It is probably involved in the rapid corrections which insure a perfect constancy of blood glucose level during the interprandial periods. R EFERENCE NOTE
1. Servant, J. M., Louis-Sylvestre, J., Molimard, R., & Le Magnen, J . Food intake in rats with portacaval anastamosis. 6th International Conference on the Physiology of Food and Fluid Intake. Jouy en Josas (France), 1977.
148
J. LOU IS-SYL V[STRE RI+E RE~CES
Bellinger, L. L., Trietley, G. J., & Bernardis, L. L. Failure of portal glucose and adrenaline infusions or liver denervation to affect food intake in dogs. Physiology and Behavior, 1976, 16,299- 304. Fuller, R. W., & Diller, E. R. Diurn a l variation ofliver glycogen a nd plasma free fatty acids in rats fed ad libitum or single daily meal. Metabolism, 1970,19,226- 229. Gagliardino, J. J., Pessacq , M. T., Hernandez, R. E., & Rebolledo, O. R. Circadian variations in serum glucagon and hepatic glucogen and cyclic AMP concentrations. Journal of EI/(Iocrill%ql' 1978. 78,297- 298. Le Magnen, J ., & Devos, M. Variations of meal to meal li ver glycogen in rats . Neuroscience LInd Biobehavioral Reviews, 1980, 4 (SuppJ. 1),29-32 Louis-Sylvestre, J., Servant, J . M ., Molimard, R. , & Le Magnen, J. Effect of li ve r denerva tion on the feeding pattern of rats. AmeriUlIl JOUf/1a/ of Phl'si%gl', 1980, 239, R66- R70. Louis-Sylvestre, J., & Le Magnen, J. A fall in blood glucose level precedes meal onset in free feeding rats. Neuroscience and Biobehavioral Reviews, 1980,4 (SuppJ. 1), 13-15. Niijima, A. Glucose sensitive afferent nerve fibers in the liver and regulation of blood glucose . Brain Research Bulletin, 1980,5 (Suppl. 4), 1-5. Novin, D., Sanderson, J. D., & Va nderWeele, D. A. The effect of isotonic glucose on eating as a function of feeding condition and infusion site. Phl'si%{/.r ilnd Behavior, 1974, 13, 3-7. PereL J .. Macaire. I., & Chanez, M. Schedule of protein ingestion, nitrogen and energy utilization a nd circadian rhythm of hepatic glycogen, plasma corticosterone and insulin in rats. Journal of Nutrition, 1973, 103, 866-874. Rezek, M., & Novin, D. Hepatic-portal nutrient infusion: effect on feeding in intact vagotomized rabbits. America/l Journal of Phl'sioloql', 1977, 232, E 1 \9- E 130. Sawchenko, P. E. , & Friedman, M . I. Sensory functions of the li ver; a review. American JOll1'llll/ of Phl'sioloqr. 1979, 236. R5- R20 . Strubbe, J. H.,& Steffens, A. B. Blood glucose levels in portal and peripheral circulation and their re lation to food intake in the rat. Phrsi%gy and Behavior, 1977, 19, 303- 307.
R eceived 11 November, 1980