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Behavioral patterns proceeding from liver thermoreceptors
Physiology & Behavior, Vol. 26, pp. 53-59. Pergamon Press and Brain Research Publ., 1981. Printed in the U.S.A.
Behavioral Patterns Proceeding from Liver Thermoreceptors L. D I B E L L A , G. T A R O Z Z I , M. T. R O S S I A N D G. S C A L E R A Cattedra di Fisiologia Generale, Universitil di Modena, 41100 Modena, Italy R e c e i v e d 14 M a r c h 1980 DI BELLA, L., G. TAROZZI, M. T. ROSSI AND G. SCALERA. Behavioralpatterns proceedingfrom liverthermoreceptors. PHYSIOL. BEHAV. 26(1) 53--59, 1981.--Subdiaphragmatic denervated, liver heated rats eat as much and as long as subdiaphragmatic denervated, non-heated rats. This points to vagus and/or splanchnic nerve afferentation from hepatic thermoreceptors. Left abdomen heated rats eat and drink as much as left abdomen non-heated rats. Since however they show some different behavior patterns, the intervention of other nerve fibers other than vagal and/or splanchnic fibers should be acknowledged in order to account for the different behavior pattern. Behavior Splanchnic
Thermoreceptors Glucoreceptors Vagus Hypothalamus
Ammonioreceptors
THE lowering of the "hunger drive," such as appears following liver heating within physiological limits, has been interpreted as being due to stimulation of liver thermoreceptor endings [12]; indeed several abdominal visceral receptors are in a position such as to affect feeding behavior. Such a functional connection was at first thought to be between the gastric contraction both in fasting conditions (hunger contraction) [10,31], and during insulin hypogiycaemia [8, 1I, 24, 27, 55]. The hunger or satiety perception has therefore been ascribed to gastric tension receptors [36]. Since no "in parallel" tension receptor has been found in viscera [31], "in series", tension receptors are involved, not however stretch or volume receptors that are brought into action during visceral smooth muscle isometric or isotonic contractions. In ruminants low threshold tension receptors exert an excitatory effect on the "gastric centers," whereas high threshold tension receptors exert an inhibitory effect on the same centers [27, 28, 31]. The gastric and bowel tension receptors supply the hypothalamic feeding centers with a pattern of information. The experimental and clinical observation, that hunger sensation and feeding behavior continue after removal or denervation of the stomach [9], does not mean that Cannon and Washburn's hypothesis is erroneous, but only that other mechanisms can supersede the gastric ones. The satiety sensation that follows ingestion of a meal is brought about by gastric f'flling [21, 22, 29, 30]. Hypothalamic "satiety" and "hunger" centers show selective changes of their electrical activity according to the magnitude of gastric distention [2,46]. "Satiety center" units respond with an increase in their spike frequency on distention, but not on compression, of the gastric walls; on the contrary, "feeding centers" respond with a decrease in their spike frequency under the same conditions. Other hypothalamic areas do not respond at all [2]. The stimulation of gastric vagal branches produces an increase in spike frequency of the "satiety center," but a
Hunger
Satiety
Liver
decrease in the "feeding center," and no response at all in other hypothalamic regions. It can be concluded that gastric "in series" tension receptors are in a position such as to modulate feeding and "satiety" hypothalamic activity through the vagal branches from the gastric walls. Most investigations on the abdominal visceral receptors have been especially concerned with mechanoreceptors, although the existence of nocireceptors, thermoreceptors and osmoreceptors has been reliably, even if indirectly, verified. An important question is whether two or more populations of receptors, with different thresholds, respond by the same physiological mechanism to the same kind of stimulus exerted by different physiological mechanisms [3 I]. Quite apart from the mesenteric Pacinian corpuscles, and from the porta-caval histologically verified receptors [13], the proof of existence of other abdominal receptors is only indirect or even incomplete. The existence of abdominal thermoreceptors in the ewe seems to be sufficiently proved [37, 38, 39, 40, 41], even though any histological proof is lacking. The abdominal thermoreceptors signal to the hypothalamus the temperature changes through the splanchnic nerve fibers; the presumed seat of the thermoreceptors probably lies within the walls of both the rumen and the intestine, as well as within the walls of the mesenteric veins. The rabbit [42] and the squirrel monkey [1] also have abdominal thermoreceptors, which have been thought to carry out a precise role in thermoregulatory reactions. Some dependent relationship between abdominal thermoreceptors and liver heat production [15, 18, 20, 54] is very likely; no steady relation appears however to exist between rectal and liver temperature [18,20]. Several histological, electrophysiological and behavioral proofs of the existence of liver thermoreceptors [16,45] are open to criticism. Liver receptors have been differentiated histologically [56] into: bare endings, within the liver lobules and around the central vein and biliary ducts; encapsulated
Copyright © 1981 Brain R e s e a r c h Publications Inc.m0031-9384/81/010053-07502.00/0
54
DI B E L L A ET AL. TABLE 1 TOTAL FOOD AND FLUID INTAKE (g), AND TOTAL TIME (see) DEVOTED DURING A 1 HR EXPERIMENT TO FOOD
AND FLUID INTAKE BY RATS HEATEDIN THE LEFT ABDOMEN,(MEAN± SD)
LAHR
Food
Water
Saline
(g)
(g)
(g)
3.562_+3.266 2.187_+1.905
LANHR 4.750_+2.206
43.
e a
1.687_+1.493
Eating (see)
Water (sec)
Saline (soc)
568.375__.468.142 72.375___107.641
35.250__.57.179
1.250_+1.064 2.250_+1.612 1010.120_+362.534 14.125__.46,092 56.250_+95.460
~'e"~haatad
rats
D
rats
control
I
1900-
ilb"4~heatad [" l c o ~ r o i
rats
rats
soo.
D
i O-
O. food
intake
water
intake
saline intake
food
intake
water
intake
saline intake
FIG. 1. Total food and fluid intake (g; M - SD) by left abdomen heated (LAHR) and non-heated (LANHR) control rats, during a I hr experiment.
FIG. 2. Total time (see; M -+ SD) devoted to food and fluid intake by left abdomen heated (LAHR) and left abdomen non-heated (LANHR) control rats, during a 1 hr experiment.
endings (Pacinian corpuscles) in the connective tissue; clubshaped and splayed glomerular endings. Physiological as well as electrophysiologlcal criteria have provided'evidence that liver gluco- as well as ammonio-receptors play a role in the regulation of food and fluid intake [34, 43, 44]; however, the results require a suitable validation [3, 4, 17, 33, 45, 53, 57]. The liver is an actively thermogenetic abdominal viscus. In the dog under basal metabolic conditions it contributes 25% of the total heat production [5]. The human liver can produce 12-18% of the total body heat production [6] or 156-234 cal/min [19]. Since dogs show a negative linear correlation between liver heat production and ambient temperature [5], and rats make use of the liver in non-shivering thermogenesis [54], it can be concluded that the liver takes an active part in the thermoregulatory reactions of such homeotherms. This liver activity is conditioned and controlled by the sympathetic nervous sytem [7, 23, 25]. The efferent nerve fibers show adrenergic endings and varicosities in close proximity to the hepatocytes, the Kuppfer cells and the liver endothelial lining cells [16]. These adrenergic endings are certainly responsible for the hyperglycemic response which adrenalectomized calves,
dogs and cats exhibit to splanchnic nerve stimulation [14]. Human liver tissue, too, contains adrenergic nerve terminals, which penetrate into the lobuli, surround single hepatocytes and run along both portal and hepatic blood vessels [35]. Preoperative stimulation of hepatic sympathetic nerves, dissected from the hepatic artery, causes an increase in plasma glucose concentration, although to a somewhat lesser extent than in cats, dogs, pigs, and calves. The increase in plasma glucose concentration after stimulation of the sympathetic liver nerves is a result of the activation of liver glycogenolytic enzymes [48,50]. Identical results to those already described are reached following ventromedial hypothalamic nuclei stimulation or norepinephrine injection [32, 47, 51], whereas electrical stimulation of lateral hypothalamic nuclei, through the vagal pathway, activates glycogen synthetase and enhances liver glycogenosis [49,52]. The conclusion follows that the liver is an important factor in temperature regulation. Food intake can be considered to be another feature of thermoregulation: both have common hypothalamic integrative centers, common peripheral sensory organs, and common autonomic nervous fibers. Hepatic thermoreceptors
BEHAVIORAL PATTERNS FROM LIVER THERMORECEPTORS
55
TABLE 2 TOTAL TIME (sec) DEVOTED DURING A I HR EXPERIMENT TO 6 BEHAVIORAL PATFERNS, BY RATS HEATED IN THE LEFT ABDOMEN AND CONTROL RATS, (MEAN - SD) Smelling
Drowsiness
Immobility
Moving
Purposeless chewing
168.600±204.800
135.80 ±130.100
603.600±305.200
72.100± 132.000
484.700±345.700
LAHR
644.700±351.100
112.200±166.700
1260.100±574.700
LANHR
237.000±307.800
626.200±554.900
1058.000±255.500
38.500± 52.700
: i
1
v
O-
smelllng
drowsiness
Fur-cleaning
immo~lit
.
ss
futr-cklanilq
]:I(3. 3. Total time (see; M ± SD) devoted to 6 behavioral patterns by left abdomen heated (LAHR) and left abdomen non-heated (LANHR) control rats, dur~,lg a 1 hr experiment.
might perfectly subserve the two functions of thermoregulation and food intake. It would therefore be worthwhile to inquire whether or not thermoreceptors are present in the fiver. METHOD
A first group of 7 male Wistar rats, weighing 220 _ 14.34 g, fed a complete and balanced diet, with water and saline solution (NaCI 0.045 M) ad lib, were operated on by placing the warming probe within the left rather than the right abdomen [12]. Food and fluid intake as well as the behavior pattern were observed during 1 hr at the end of an 8 hr fasting period. These left abdomen heated rats (LAHR) served as their own control (LANHR), in following experiments; not less than 48 hr elapsed between two successive experiments. These rats showed a mean daily weight gain of4.15 ± 0.349 g and a mean daily food intake of 20.975 _ 0.5 g after the operation, during the whole experimental period. A second group of 18 male Wistar rats, weighing 141.00 ± 15.19 g, kept in the same ambient conditions were operated on by sectioning the splanchnic and vagus nerve fibers close to the esophagus and the abdominal aorta and by
placing the warming probe against the liver, as usual [12]. Out of 18 operated rats only 8 rats were judged to be in satisfactory conditions and used for the successive experiments. The experiments were started after the rats had recovered from the operative stress and had begun normal eating and drinking. At this time the rats weighed 247.25 _ 22.78 g; in the meantime their mean daily weight gain was 3.90 ± 0.754 g, and their daily food intake was 20.071 _ 0.847 g. The probe position, the conditions of the peritoneal serous membrane, the appearance, position, and mutual relations between the stomach, the bowel and the liver were checked at the end of the experiments. In this second series of experiments a comparison was made between the subdiaphragrnatically denervated heated rats (SDHR), and the subdiaphragmatically denervated non-heated rats (SDNHR). Here, too, SDHR served as their own control (SDNHR), in subsequent experiments, performed at not less than 48 hr intervals. The abdomen was heated with the warming probe, at a temperature not higher than 42°C, for an hour, after 8 hr fasting. During the experiments the rats were kept in their own cages whether or not the probe they carried was heated.
DI B E L L A ET AL.
56 TABLE 3
TOTAL FOOD AND FLUID INTAKE (8), AND TOTAL TIME (sec) DEVOTED TO FOOD AND FLUID INTAKE FOLLOWING SUBDIAPHRAGMATIC DENERVATION, (MEAN ± SD), DURING A 1 HR EXPERIMENT
Food (g)
Water (g)
Saline (g)
Eating (sec)
Water (sec)
Saline (sec)
2.333+_2.352
721.000_+605.261
38.111±65.516
80.222_+94.442
893.611_+472.492
61.444_+71.343 77.222_.+89.739
SDHR
3.388_+2.661
1.111±1.567
SDNHR
4.111±2.054
1.388_+1.378 2.555±2.640
TABLE 4 TOTAL TIME (sec) DEVOTED DURING A 1 HR EXPERIMENT TO 6 BEHAVIORAL PATI'ERNS FOLLOWING SUBDIAPHRAGMATIC DENERVATION, (MEAN ± SD)
Smelling
Drowsiness
Immobility
Moving
SDHR
563.444_+420.239
380.777_+311.791
1528.666+_452.451
46.880+_52.181
64.110+_80.770
290.222-+281.500
SDNHR
376.111-+267.612
550.333-+568.131
925.777+_542.696 60.888-+58.487
36.444_+73.866
560.555+_369.741
RESULTS
Purposeless chewing
+
Heating in the Left Abdomen The results are reported in Table 1. F o o d intake is lower, but not significantly, in the L A H R than in the L A N H R , which served as control; not even the volume of water and saline drunk are significantly different (Fig. 1). The time spent in food intake is significantly shorter, and the time devoted to water drinking is significantly longer in L A H R than in L A N H R or control rat (Fig. 2). The length of time that were devoted to the single behavior pattern are reported in Table 2. The length of time spent in smelling and in moving about are longer, while those spent in drowsiness are shorter in heated (LAHR) than in non-heated (LANHR) control rats. Immobility as well as purposeless chewing and fur cleaning last as long in L A H R as in L A N H R control rats (Fig. 3).
'~heated
s. (.
CONCLUSIONS
Sectioning the subdiaphragmatic fibers of splanchnic and vagus nerves makes the heated rats (SDHR) behave like the non-heated ones (SDNHR). In this case the direct effect of probe heat on the liver is not responsible for the decreased food intake as found in normal non-denervated rats in the same experimental conditions [12]. The cause of the reduction of food intake might rather be the stimulation of liver receptors and the conduction of the excitement through the
rats
[~c
e.
ontrol r a t s
I
3.
2. 1.
Liver Heating after Subdiaphragmatic Denervation Subdiaphragmatic denervation was well tolerated. The feeding and drinking behavior of denervated, heated rats (SDHR) is shown in Table 3. Food, water and saline intakes, as well as length of time, are not significantly different in SDHR than in SDNHR control rats (Figs. 4 and 5). The time spent in the different behavior patterns is shown in Table 4. SDHR spent a longer time in immobility and a shorter time in fur-cleaning than SDNHR control rats (Fig. 6).
Fur-cleaning
O.
I food intake
water intake
saline intake
HG. 4. Total food and fluid intake (g; M _+ SD) by subdiaphragmatically denervated heated (SDHR) and subdiaphragmatically denervated non-heated (SDNHR) control rats, during a 1 hr experiment.
splanchnic and/or the vagal subdiaphragmatic fibers. When the subdiaphragmatic nervous fibers are dissected, the feeding centers [2,46] seem to be no longer inhibited by liver heating, and the rats show a feeding behavior not significantly different from that of non-heated normal rats. Part of the heat released by the probe raises the temperature of the hepatic parenchyma, part is carried away by convection to the pulmonary circle and then probably to the great circle and to the cerebral circulation; part, at least, is conducted to the surrounding tissues.
BEHAVIORAL PATTERNS FROM LIVER THERMORECEPTORS
.! ~ ' ~ h e a l e d rats IOOG. [ " ~ c o n t r o l rats
food
intake
water intmke
iIIline intake
FIG. 5. Total time (sex; M ± SD) devoted to food and fluid intake by subdiaphragmatically denervated heated (SDHR) and subdiaphragmatically denervated non-heated (SDNH) control rats, during a 1 hr experiment. The slightly overnormal amount of heat that reaches the lung tissue during heating by the probe is probably completely given up in the air exhaled and perhaps only negligible traces are convected to the cerebral arterial blood, so that neither the feeding integrative centers nor the thermoregulatory ones are functionally impaired. The heat released by the warming probe during a one-
l
!
smelling
hour experiment was 467.937 _+ 79.983 cal. Since only one disk surface of the probe touched the liver, even in the worst conditions of hepatic blood circulation and thermic conductance to the surrounding tissues, the liver temperature would have risen gradually in the course of a one-hour experiment by no more than 5°C. Even if the heat released by the probe had instantaneously diffused to the whole organism (making the specific heat of body equal to 0.9) the body temperature of the rat would have gradually risen by 0.5-1°C depending on its body weight. All things considered, neither liver nor body temperature had risen so much as to injure the liver parenchyma or to impair the body functions. Since either water and saline volume, or food intake, as well as saline drinking time are as high in SDHR as in SDNHR, the conclusion can be drawn that in the aforesaid conditions the behavioral patterns are not significantly influenced by liver temperature. These experimental results point to the existence of liver thermoreceptors, which may be afferented to feeding and drinking behavior centers through the splanchnic and/or the vagal subdiaphragmatic fibers. Denervated heated rats (SDHR) drink as much NaCl solution as non-denervatod (SDNHR) control rats; the results may be interpreted as if the salt-taste tongue afferences were more powerful than liver thermoreceptive inputs in stimulating drinking centers. Left abdomen heated rats (LAHR) eat as much as left abdomen non-heated control rats (LANHR); they spend, however, a significantly shorter time in eating than the nonheated control rats (LANHR): it follows that LAHR eat more quickly than LANHR. The experimental results point to a double food intake regulation mechanism: one acting on food intake amount, the other on food intake speed. Liver thermoreceptors act only or mostly on the first mechanism. A different group of ther-
"
•
0.
57
drowliaeu
immlbllit
!
t
reeving
i
fu~lllmllll
FIG. 6. Total time (sex; M - SD) devoted to six behavioral patterns by subdiaphragmatically denervated heated (SDHR) and subdiaphrngmaticallydenervated non-heated (SDNHR) control rats, during a 1 hr experiment.
58
DI B E L L A E T A L .
morcceptors, which is present in the left abdomen organs, might on the contrary modify food intake speed. Left abdomen heated rats (LAHR) however drink water more slowly than liver heated rats [12]. These results also point to a different influence of left and right abdomen thermoreceptors on food and fluid intake. The length of time of a few non-drinking-, non-feeding behavior patterns, that follows from right abdomen heating, remains unchanged whether or not denervation is performed. Both receptors and nerve fibers are therefore probably different from liver thermorcceptors and from splanchnic and vagus abdominal nerve fibers. The afferences from these behavioral aspects are most probably effected by the phrenicus nerve, and/or by the final intercostal nerve fibers. The time rats devote to smelling, to purposeless chewing, to drowsiness, or to moving about, does not change significantly after subdiaphragmatic denervation; the immobility
time is lengthened, the fur-cleaning time shortened, both significantly. In conclusion a normal increase in liver temperature, probably independently of its determining factors, must be included among the short-term regulating factors of food and fluid intake. The food intake inhibition is afferented through the splanchnic and/or the vagus subdiaphragmatic fibers. The same fibers as well as other ones from phrenic or intercostal nerves probably intervene in simultaneously governing some behavioral attitudes. ACKNOWLEDGEMENTS We are most grateful to Mr. Fausto Vaccari for his expert technical suggestions and assistance, and his active participation in various aspects of this study.
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59
47. Shimazu, T., A. Fukuda and T. Ban. Reciprocal influences of the ventromedial and lateralhypothalamic nuclei on blood glucose level and liverglycogen content. Nature 210:1178-I 179, 1966. 48. Shimazu, T. and A. Amakawa. Regulation of glycogen metabolism in liverby the autonomic nervous system. II--Neural control of glycogenolytic enzymes. Biochim. biophys. Acta 165: 335-348, 1968. 49. Shimazu, T. Regulation of glycogen metabolism in liverby the autonomic nervous system. V--Activation of glycogen syntherase by vagal stimulation.Biochim. biophys. Acta. 252: 28--38, 1971. 50. Shimazu, T. and A. Amakawa. Regulation of glycogen metabolism in liver by the autonomic nervous system. VI--Possible mechanism of phosphorilase activationby the splanchnic nerve. Biochim. Biophys. Act. 385: 242-256, 1975. 51. Shimazu, T. and S. Ogasawara. Effect of hypothalamic stimulation on gluconeogenesis and glycolysis in rat liver. Am. J. Physiol. 228: 1787-1793, 1975. 52. Shimazu, T., H. Matsushita and K. Ishikawa. Cholinergic stimulation of the rat hypothalamus: effect on liver glycogen synthesis. Science 194: 535-536, 1976. 53. Stephens, D. B. and B. A. Baldwin. The lack of effect of intrajugular or intraportal injections of glucose or amino acids on food intake in pig. Physiol. Behav. 12: 923--929, 1974. 54. Stoner, H. B. The role of the liver in non-sldvering thermogenesis in the rat. J. Physiol., Lond. 232: 285-296, 1973. 55. Thomas, J. E. Mechanics and regulation of gastric emptying. Physiol. Rev. 37: 453-474, 1957. 56. Tsal, T. L. A histological study of the sensory nerves in the liver. Acta Neuroveg. 17: 354-385, 1958. 57. VanderWeele, D. A., D. Novin, M. Rezek and J. D. Saunderson. Duodenal or hepatic-portal glucose perfusion: evidence for duodenally-based satiety. Physiol. Behav. 12" 467--473, 1974.
Behavioral Patterns Proceeding from Liver Thermoreceptors L. D I B E L L A , G. T A R O Z Z I , M. T. R O S S I A N D G. S C A L E R A Cattedra di Fisiologia Generale, Universitil di Modena, 41100 Modena, Italy R e c e i v e d 14 M a r c h 1980 DI BELLA, L., G. TAROZZI, M. T. ROSSI AND G. SCALERA. Behavioralpatterns proceedingfrom liverthermoreceptors. PHYSIOL. BEHAV. 26(1) 53--59, 1981.--Subdiaphragmatic denervated, liver heated rats eat as much and as long as subdiaphragmatic denervated, non-heated rats. This points to vagus and/or splanchnic nerve afferentation from hepatic thermoreceptors. Left abdomen heated rats eat and drink as much as left abdomen non-heated rats. Since however they show some different behavior patterns, the intervention of other nerve fibers other than vagal and/or splanchnic fibers should be acknowledged in order to account for the different behavior pattern. Behavior Splanchnic
Thermoreceptors Glucoreceptors Vagus Hypothalamus
Ammonioreceptors
THE lowering of the "hunger drive," such as appears following liver heating within physiological limits, has been interpreted as being due to stimulation of liver thermoreceptor endings [12]; indeed several abdominal visceral receptors are in a position such as to affect feeding behavior. Such a functional connection was at first thought to be between the gastric contraction both in fasting conditions (hunger contraction) [10,31], and during insulin hypogiycaemia [8, 1I, 24, 27, 55]. The hunger or satiety perception has therefore been ascribed to gastric tension receptors [36]. Since no "in parallel" tension receptor has been found in viscera [31], "in series", tension receptors are involved, not however stretch or volume receptors that are brought into action during visceral smooth muscle isometric or isotonic contractions. In ruminants low threshold tension receptors exert an excitatory effect on the "gastric centers," whereas high threshold tension receptors exert an inhibitory effect on the same centers [27, 28, 31]. The gastric and bowel tension receptors supply the hypothalamic feeding centers with a pattern of information. The experimental and clinical observation, that hunger sensation and feeding behavior continue after removal or denervation of the stomach [9], does not mean that Cannon and Washburn's hypothesis is erroneous, but only that other mechanisms can supersede the gastric ones. The satiety sensation that follows ingestion of a meal is brought about by gastric f'flling [21, 22, 29, 30]. Hypothalamic "satiety" and "hunger" centers show selective changes of their electrical activity according to the magnitude of gastric distention [2,46]. "Satiety center" units respond with an increase in their spike frequency on distention, but not on compression, of the gastric walls; on the contrary, "feeding centers" respond with a decrease in their spike frequency under the same conditions. Other hypothalamic areas do not respond at all [2]. The stimulation of gastric vagal branches produces an increase in spike frequency of the "satiety center," but a
Hunger
Satiety
Liver
decrease in the "feeding center," and no response at all in other hypothalamic regions. It can be concluded that gastric "in series" tension receptors are in a position such as to modulate feeding and "satiety" hypothalamic activity through the vagal branches from the gastric walls. Most investigations on the abdominal visceral receptors have been especially concerned with mechanoreceptors, although the existence of nocireceptors, thermoreceptors and osmoreceptors has been reliably, even if indirectly, verified. An important question is whether two or more populations of receptors, with different thresholds, respond by the same physiological mechanism to the same kind of stimulus exerted by different physiological mechanisms [3 I]. Quite apart from the mesenteric Pacinian corpuscles, and from the porta-caval histologically verified receptors [13], the proof of existence of other abdominal receptors is only indirect or even incomplete. The existence of abdominal thermoreceptors in the ewe seems to be sufficiently proved [37, 38, 39, 40, 41], even though any histological proof is lacking. The abdominal thermoreceptors signal to the hypothalamus the temperature changes through the splanchnic nerve fibers; the presumed seat of the thermoreceptors probably lies within the walls of both the rumen and the intestine, as well as within the walls of the mesenteric veins. The rabbit [42] and the squirrel monkey [1] also have abdominal thermoreceptors, which have been thought to carry out a precise role in thermoregulatory reactions. Some dependent relationship between abdominal thermoreceptors and liver heat production [15, 18, 20, 54] is very likely; no steady relation appears however to exist between rectal and liver temperature [18,20]. Several histological, electrophysiological and behavioral proofs of the existence of liver thermoreceptors [16,45] are open to criticism. Liver receptors have been differentiated histologically [56] into: bare endings, within the liver lobules and around the central vein and biliary ducts; encapsulated
Copyright © 1981 Brain R e s e a r c h Publications Inc.m0031-9384/81/010053-07502.00/0
54
DI B E L L A ET AL. TABLE 1 TOTAL FOOD AND FLUID INTAKE (g), AND TOTAL TIME (see) DEVOTED DURING A 1 HR EXPERIMENT TO FOOD
AND FLUID INTAKE BY RATS HEATEDIN THE LEFT ABDOMEN,(MEAN± SD)
LAHR
Food
Water
Saline
(g)
(g)
(g)
3.562_+3.266 2.187_+1.905
LANHR 4.750_+2.206
43.
e a
1.687_+1.493
Eating (see)
Water (sec)
Saline (soc)
568.375__.468.142 72.375___107.641
35.250__.57.179
1.250_+1.064 2.250_+1.612 1010.120_+362.534 14.125__.46,092 56.250_+95.460
~'e"~haatad
rats
D
rats
control
I
1900-
ilb"4~heatad [" l c o ~ r o i
rats
rats
soo.
D
i O-
O. food
intake
water
intake
saline intake
food
intake
water
intake
saline intake
FIG. 1. Total food and fluid intake (g; M - SD) by left abdomen heated (LAHR) and non-heated (LANHR) control rats, during a I hr experiment.
FIG. 2. Total time (see; M -+ SD) devoted to food and fluid intake by left abdomen heated (LAHR) and left abdomen non-heated (LANHR) control rats, during a 1 hr experiment.
endings (Pacinian corpuscles) in the connective tissue; clubshaped and splayed glomerular endings. Physiological as well as electrophysiologlcal criteria have provided'evidence that liver gluco- as well as ammonio-receptors play a role in the regulation of food and fluid intake [34, 43, 44]; however, the results require a suitable validation [3, 4, 17, 33, 45, 53, 57]. The liver is an actively thermogenetic abdominal viscus. In the dog under basal metabolic conditions it contributes 25% of the total heat production [5]. The human liver can produce 12-18% of the total body heat production [6] or 156-234 cal/min [19]. Since dogs show a negative linear correlation between liver heat production and ambient temperature [5], and rats make use of the liver in non-shivering thermogenesis [54], it can be concluded that the liver takes an active part in the thermoregulatory reactions of such homeotherms. This liver activity is conditioned and controlled by the sympathetic nervous sytem [7, 23, 25]. The efferent nerve fibers show adrenergic endings and varicosities in close proximity to the hepatocytes, the Kuppfer cells and the liver endothelial lining cells [16]. These adrenergic endings are certainly responsible for the hyperglycemic response which adrenalectomized calves,
dogs and cats exhibit to splanchnic nerve stimulation [14]. Human liver tissue, too, contains adrenergic nerve terminals, which penetrate into the lobuli, surround single hepatocytes and run along both portal and hepatic blood vessels [35]. Preoperative stimulation of hepatic sympathetic nerves, dissected from the hepatic artery, causes an increase in plasma glucose concentration, although to a somewhat lesser extent than in cats, dogs, pigs, and calves. The increase in plasma glucose concentration after stimulation of the sympathetic liver nerves is a result of the activation of liver glycogenolytic enzymes [48,50]. Identical results to those already described are reached following ventromedial hypothalamic nuclei stimulation or norepinephrine injection [32, 47, 51], whereas electrical stimulation of lateral hypothalamic nuclei, through the vagal pathway, activates glycogen synthetase and enhances liver glycogenosis [49,52]. The conclusion follows that the liver is an important factor in temperature regulation. Food intake can be considered to be another feature of thermoregulation: both have common hypothalamic integrative centers, common peripheral sensory organs, and common autonomic nervous fibers. Hepatic thermoreceptors
BEHAVIORAL PATTERNS FROM LIVER THERMORECEPTORS
55
TABLE 2 TOTAL TIME (sec) DEVOTED DURING A I HR EXPERIMENT TO 6 BEHAVIORAL PATFERNS, BY RATS HEATED IN THE LEFT ABDOMEN AND CONTROL RATS, (MEAN - SD) Smelling
Drowsiness
Immobility
Moving
Purposeless chewing
168.600±204.800
135.80 ±130.100
603.600±305.200
72.100± 132.000
484.700±345.700
LAHR
644.700±351.100
112.200±166.700
1260.100±574.700
LANHR
237.000±307.800
626.200±554.900
1058.000±255.500
38.500± 52.700
: i
1
v
O-
smelllng
drowsiness
Fur-cleaning
immo~lit
.
ss
futr-cklanilq
]:I(3. 3. Total time (see; M ± SD) devoted to 6 behavioral patterns by left abdomen heated (LAHR) and left abdomen non-heated (LANHR) control rats, dur~,lg a 1 hr experiment.
might perfectly subserve the two functions of thermoregulation and food intake. It would therefore be worthwhile to inquire whether or not thermoreceptors are present in the fiver. METHOD
A first group of 7 male Wistar rats, weighing 220 _ 14.34 g, fed a complete and balanced diet, with water and saline solution (NaCI 0.045 M) ad lib, were operated on by placing the warming probe within the left rather than the right abdomen [12]. Food and fluid intake as well as the behavior pattern were observed during 1 hr at the end of an 8 hr fasting period. These left abdomen heated rats (LAHR) served as their own control (LANHR), in following experiments; not less than 48 hr elapsed between two successive experiments. These rats showed a mean daily weight gain of4.15 ± 0.349 g and a mean daily food intake of 20.975 _ 0.5 g after the operation, during the whole experimental period. A second group of 18 male Wistar rats, weighing 141.00 ± 15.19 g, kept in the same ambient conditions were operated on by sectioning the splanchnic and vagus nerve fibers close to the esophagus and the abdominal aorta and by
placing the warming probe against the liver, as usual [12]. Out of 18 operated rats only 8 rats were judged to be in satisfactory conditions and used for the successive experiments. The experiments were started after the rats had recovered from the operative stress and had begun normal eating and drinking. At this time the rats weighed 247.25 _ 22.78 g; in the meantime their mean daily weight gain was 3.90 ± 0.754 g, and their daily food intake was 20.071 _ 0.847 g. The probe position, the conditions of the peritoneal serous membrane, the appearance, position, and mutual relations between the stomach, the bowel and the liver were checked at the end of the experiments. In this second series of experiments a comparison was made between the subdiaphragrnatically denervated heated rats (SDHR), and the subdiaphragmatically denervated non-heated rats (SDNHR). Here, too, SDHR served as their own control (SDNHR), in subsequent experiments, performed at not less than 48 hr intervals. The abdomen was heated with the warming probe, at a temperature not higher than 42°C, for an hour, after 8 hr fasting. During the experiments the rats were kept in their own cages whether or not the probe they carried was heated.
DI B E L L A ET AL.
56 TABLE 3
TOTAL FOOD AND FLUID INTAKE (8), AND TOTAL TIME (sec) DEVOTED TO FOOD AND FLUID INTAKE FOLLOWING SUBDIAPHRAGMATIC DENERVATION, (MEAN ± SD), DURING A 1 HR EXPERIMENT
Food (g)
Water (g)
Saline (g)
Eating (sec)
Water (sec)
Saline (sec)
2.333+_2.352
721.000_+605.261
38.111±65.516
80.222_+94.442
893.611_+472.492
61.444_+71.343 77.222_.+89.739
SDHR
3.388_+2.661
1.111±1.567
SDNHR
4.111±2.054
1.388_+1.378 2.555±2.640
TABLE 4 TOTAL TIME (sec) DEVOTED DURING A 1 HR EXPERIMENT TO 6 BEHAVIORAL PATI'ERNS FOLLOWING SUBDIAPHRAGMATIC DENERVATION, (MEAN ± SD)
Smelling
Drowsiness
Immobility
Moving
SDHR
563.444_+420.239
380.777_+311.791
1528.666+_452.451
46.880+_52.181
64.110+_80.770
290.222-+281.500
SDNHR
376.111-+267.612
550.333-+568.131
925.777+_542.696 60.888-+58.487
36.444_+73.866
560.555+_369.741
RESULTS
Purposeless chewing
+
Heating in the Left Abdomen The results are reported in Table 1. F o o d intake is lower, but not significantly, in the L A H R than in the L A N H R , which served as control; not even the volume of water and saline drunk are significantly different (Fig. 1). The time spent in food intake is significantly shorter, and the time devoted to water drinking is significantly longer in L A H R than in L A N H R or control rat (Fig. 2). The length of time that were devoted to the single behavior pattern are reported in Table 2. The length of time spent in smelling and in moving about are longer, while those spent in drowsiness are shorter in heated (LAHR) than in non-heated (LANHR) control rats. Immobility as well as purposeless chewing and fur cleaning last as long in L A H R as in L A N H R control rats (Fig. 3).
'~heated
s. (.
CONCLUSIONS
Sectioning the subdiaphragmatic fibers of splanchnic and vagus nerves makes the heated rats (SDHR) behave like the non-heated ones (SDNHR). In this case the direct effect of probe heat on the liver is not responsible for the decreased food intake as found in normal non-denervated rats in the same experimental conditions [12]. The cause of the reduction of food intake might rather be the stimulation of liver receptors and the conduction of the excitement through the
rats
[~c
e.
ontrol r a t s
I
3.
2. 1.
Liver Heating after Subdiaphragmatic Denervation Subdiaphragmatic denervation was well tolerated. The feeding and drinking behavior of denervated, heated rats (SDHR) is shown in Table 3. Food, water and saline intakes, as well as length of time, are not significantly different in SDHR than in SDNHR control rats (Figs. 4 and 5). The time spent in the different behavior patterns is shown in Table 4. SDHR spent a longer time in immobility and a shorter time in fur-cleaning than SDNHR control rats (Fig. 6).
Fur-cleaning
O.
I food intake
water intake
saline intake
HG. 4. Total food and fluid intake (g; M _+ SD) by subdiaphragmatically denervated heated (SDHR) and subdiaphragmatically denervated non-heated (SDNHR) control rats, during a 1 hr experiment.
splanchnic and/or the vagal subdiaphragmatic fibers. When the subdiaphragmatic nervous fibers are dissected, the feeding centers [2,46] seem to be no longer inhibited by liver heating, and the rats show a feeding behavior not significantly different from that of non-heated normal rats. Part of the heat released by the probe raises the temperature of the hepatic parenchyma, part is carried away by convection to the pulmonary circle and then probably to the great circle and to the cerebral circulation; part, at least, is conducted to the surrounding tissues.
BEHAVIORAL PATTERNS FROM LIVER THERMORECEPTORS
.! ~ ' ~ h e a l e d rats IOOG. [ " ~ c o n t r o l rats
food
intake
water intmke
iIIline intake
FIG. 5. Total time (sex; M ± SD) devoted to food and fluid intake by subdiaphragmatically denervated heated (SDHR) and subdiaphragmatically denervated non-heated (SDNH) control rats, during a 1 hr experiment. The slightly overnormal amount of heat that reaches the lung tissue during heating by the probe is probably completely given up in the air exhaled and perhaps only negligible traces are convected to the cerebral arterial blood, so that neither the feeding integrative centers nor the thermoregulatory ones are functionally impaired. The heat released by the warming probe during a one-
l
!
smelling
hour experiment was 467.937 _+ 79.983 cal. Since only one disk surface of the probe touched the liver, even in the worst conditions of hepatic blood circulation and thermic conductance to the surrounding tissues, the liver temperature would have risen gradually in the course of a one-hour experiment by no more than 5°C. Even if the heat released by the probe had instantaneously diffused to the whole organism (making the specific heat of body equal to 0.9) the body temperature of the rat would have gradually risen by 0.5-1°C depending on its body weight. All things considered, neither liver nor body temperature had risen so much as to injure the liver parenchyma or to impair the body functions. Since either water and saline volume, or food intake, as well as saline drinking time are as high in SDHR as in SDNHR, the conclusion can be drawn that in the aforesaid conditions the behavioral patterns are not significantly influenced by liver temperature. These experimental results point to the existence of liver thermoreceptors, which may be afferented to feeding and drinking behavior centers through the splanchnic and/or the vagal subdiaphragmatic fibers. Denervated heated rats (SDHR) drink as much NaCl solution as non-denervatod (SDNHR) control rats; the results may be interpreted as if the salt-taste tongue afferences were more powerful than liver thermoreceptive inputs in stimulating drinking centers. Left abdomen heated rats (LAHR) eat as much as left abdomen non-heated control rats (LANHR); they spend, however, a significantly shorter time in eating than the nonheated control rats (LANHR): it follows that LAHR eat more quickly than LANHR. The experimental results point to a double food intake regulation mechanism: one acting on food intake amount, the other on food intake speed. Liver thermoreceptors act only or mostly on the first mechanism. A different group of ther-
"
•
0.
57
drowliaeu
immlbllit
!
t
reeving
i
fu~lllmllll
FIG. 6. Total time (sex; M - SD) devoted to six behavioral patterns by subdiaphragmatically denervated heated (SDHR) and subdiaphrngmaticallydenervated non-heated (SDNHR) control rats, during a 1 hr experiment.
58
DI B E L L A E T A L .
morcceptors, which is present in the left abdomen organs, might on the contrary modify food intake speed. Left abdomen heated rats (LAHR) however drink water more slowly than liver heated rats [12]. These results also point to a different influence of left and right abdomen thermoreceptors on food and fluid intake. The length of time of a few non-drinking-, non-feeding behavior patterns, that follows from right abdomen heating, remains unchanged whether or not denervation is performed. Both receptors and nerve fibers are therefore probably different from liver thermorcceptors and from splanchnic and vagus abdominal nerve fibers. The afferences from these behavioral aspects are most probably effected by the phrenicus nerve, and/or by the final intercostal nerve fibers. The time rats devote to smelling, to purposeless chewing, to drowsiness, or to moving about, does not change significantly after subdiaphragmatic denervation; the immobility
time is lengthened, the fur-cleaning time shortened, both significantly. In conclusion a normal increase in liver temperature, probably independently of its determining factors, must be included among the short-term regulating factors of food and fluid intake. The food intake inhibition is afferented through the splanchnic and/or the vagus subdiaphragmatic fibers. The same fibers as well as other ones from phrenic or intercostal nerves probably intervene in simultaneously governing some behavioral attitudes. ACKNOWLEDGEMENTS We are most grateful to Mr. Fausto Vaccari for his expert technical suggestions and assistance, and his active participation in various aspects of this study.
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