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We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the long-chain fatty acid oleate (150 nmol/min, 24 h), the medium-chain fatty acid caprylate, or the solvent. Corticosterone (Cort) and norepinephrine (NE) were measured as indexes for HPA axis and sympathetic activity, respectively. Insulin sensitivity was assessed by means of an intravenous glucose tolerance test (IVGTT). Oleate infusion induced increases in plasma Cort (Delta = 13.5 +/- 3.6 microg/dl; P < 0.05) and NE (Delta = 235 +/- 76 ng/l; P < 0.05), whereas caprylate and solvent had no effect. The area under the insulin response curve to the IVGTT was larger in the oleate-treated group than in the caprylate and solvent groups (area = 220 +/- 35 vs. 112 +/- 13 and 106 +/- 8, respectively, P < 0.05). The area under the glucose response curves was comparable [area = 121 +/- 13 (oleate) vs. 135 +/- 20 (caprylate) and 96 +/- 11 (solvent)]. The results are consistent with the concept that increased portal free fatty acid is involved in the induction of visceral obesity-related insulin resistance via activation of the HPA axis and sympathetic system.

Chronic portal vein cannulation in the rat is an important technique to study secretory rates of hormones from the endocrine pancreas. Moreover, it can be used for studying the effects of enteric hormones and pharmaca on behavioral and physiological processes. This article contains an extensive description of a cannulation technique of the portal vein that has many advantages over those reported so far in the literature, and that was very successful in several behavioral and physiological studies during the last decade.

Data are accumulating that insulin acting in the central nervous system is a physiological regulator of food intake and body weight, presumably via its effect in the hypothalamus. The present study investigated whether infusion of a small dose of insulin into two major hypothalamic insulin-binding areas also has an effect on diet selection and behavior. At the beginning of the dark period, rats received local bilateral infusions of 4 microU of insulin or vehicle during 34 min into the arcuate (ARC) or paraventricular (PVN) nucleus of the hypothalamus. Consumption of carbohydrate (C)-, protein (P)-, and fat (F)-enriched food and time spent on certain behaviors (drinking, resting, grooming, rearing, exploring/sniffing) were assessed during the first nocturnal hour. In addition, 21-h diet selection was assessed. The percentage contribution of macronutrients (C/P/F) to total energy content of the C-, P-, and F-enriched diets was 71.9/17.2/10.9, 45.8/43.4/10.8, and 47.1/17.5/35.4, respectively. During the first hour, infusion of insulin into the PVN increased grooming behavior compared to infusion of the vehicle. Although infusion of insulin had no effect on diet selection during the first hour, insulin infused in the ARC caused a reduction in F-enriched food consumption and total intake of F (as a macronutrient) over the 21-h period without altering total food intake. Infusion of a higher dose of insulin (10 microU) into the third ventricle had no effect on any of the assessed parameters. The data are explained to indicate that insulin (being an indicator of a positive energy balance) adjusts body weight homeostasis by modulating the preference for fat, at least at the level of the ARC, but not at the PVN.

Leptin, a hormone secreted by adipose tissue in proportion to body adiposity, is proposed to be involved in the central nervous regulation of food intake and body weight. In addition, evidence is emerging that leptin regulates neuroendocrine and metabolic functions as well, presumably via its action in the central nervous system (CNS). To investigate this regulatory effect of leptin, we infused 3.5 microg of human leptin directly into the third cerebral ventricle (i3vt) of lean male Long-Evans rats, 90 min before the onset of their dark phase. Before and after infusion, blood samples were withdrawn through indwelling catheters for assessment of hormonal (plasma corticosterone, insulin, leptin), autonomic (plasma norepinephrine, epinephrine), and metabolic (plasma glucose) parameters. I3vt leptin caused an increase in plasma corticosterone and plasma leptin levels relative to the control condition. The effects of i3vt leptin on corticosterone secretion became particularly apparent after the onset of the dark phase. The results of the present study indicate that i3vt leptin stimulates the hypothalamo-pituitary-adrenal (HPA) axis, particularly when rats normally encounter their largest meals. These results are consistent with the possibility that high circulating leptin levels may underlie the increased activity of the HPA axis that is generally characteristic of human obesity and most animal models of obesity.

This study was designed 1) to investigate mechanisms of insulin secretion during exercise after transplantation of islets in the spleen and under the kidney capsule, and 2) to compare these organs as transplantation site regarding an adequate portal or systemic delivery of insulin and glucose homeostasis during exercise. Diabetic rats were provided with 5 microL isogenic islet tissue in the spleen or under the kidney capsule, which results in normoglycemia, and were submitted to a swimming test. Portal plasma insulin levels were higher than simultaneously sampled systemic insulin levels in the control and in the intrasplenic islet grafted group, but not in the kidney subcapsular islet-grafted group. Plasma portal and systemic insulin levels decreased, and glucose levels increased during exercise in all groups. The exercise-induced increase in levels of catecholamines was larger in systemic than in portal plasma, suggesting catecholamine extraction by the lungs or intestines. The experiments were repeated after removing of adrenal medulla, resulting in nondetectable or very low plasma adrenaline levels. Despite these low adrenaline levels, insulin levels decreased during exercise. The results indicate that 1) the exercise-induced reduction of insulin secretion is not mediated by circulating adrenaline, but is probably under control of the sympathetic nervous system, which could be the result of reinnervation of the transplanted islets. 2) Although a portal-systemic insulin gradient was absent in rats with kidney subcapsular islet grafts, the absence of a difference in glucose homeostasis during exercise between the sites revealed that all investigated sites are preferential to transplant islets.

Insulin-dependent diabetes mellitus is associated with altered fat and carbohydrate metabolism and disturbed sympathoadrenal functioning. The aim of this study was to investigate whether the short-term diabetic state alters the activity of the sympathoadrenal system and of the adrenal cortex during exercise. In addition, the possible reciprocal effects of a deviating sympathoadrenal functioning and an altered non-esterified fatty acid (NEFA) and glucose metabolism were investigated. Therefore, control rats, diabetic rats, and partial diabetic rats were submitted to swimming (15 minutes). Permanent heart catheters allowed frequent blood sampling without disturbing the animals. Blood glucose and plasma NEFA levels increased during exercise. partial diabetic animals showed similar effects as controls. In contrast, the glucose and NEFA increments were significantly higher in diabetic rats than in control and partial diabetic rats. During exercise, the very low insulin levels were unaltered in diabetic rats, whereas they decreased in the other groups. Exercise-induced elevations of plasma epinephrine and norepinephrine were similar in all groups, but were lower for corticosterone in the diabetic animals. Therefore, these results provide evidence that the exaggerated NEFA mobilization in diabetic rats is only the result of reduced inhibition of lipolysis by the relative lack of insulin. It is concluded that the short-term diabetic state does not alter the activity of the sympathetic nervous system during exercise, but lowers the activity of the adrenal cortex.

The influences of glucagon-like peptide-I-(7-36) amide (GLP-I; 15 mumol. kg-1.min-1) on glucose turnover were studied in freely moving Wistar rats. In fed rats, GLP-1 reduced plasma glucose (from 7.3 +/- 0.2 to 5.6 +/- 0.3 mmol/l; P = 0.017), increased plasma insulin (from 20 +/- 3 to 89 +/- 11 mU/l; P = 0.002), and reduced plasma glucagon (from 44 +/- 1 to 35 +/- 2 pg/ml; P = 0.009) and glucose appearance rate (Ra; from 3.9 +/- 0.2 to 1.7 +/- 0.7 micromol.min-1. 100 g-1 after 30 min; P = 0.049) without affecting glucose disappearance rate (Rd). The glucose clearance rate (MCR) was increased (P = 0.048). In 48-h-fasted rats, GLP-I reduced plasma glucose (from 5.0 +/- 0.2 to 4.4 +/- 0.3 mmol/l; P = 0.035) and increased plasma insulin (from 4 +/- 1 to 25 +/- 10 mU/l; P = 0.042) and plasma glucagon (from 43 +/- 3 to 61 +/- 7 pg/ml; P = 0.046). Ra and Rd were not significantly affected, although Ra was lower than Rd after 15-30 min (P = 0.005) and MCR was increased (P = 0.049). Thus GLP-I reduces Ra in fed rats and increases MCR in fed and fasted rats. The reduced Ra seems mediated by an increased insulin-to-glucagon ratio; the increased glucose clearance seems dependent on insulin and a peripheral effect of GLP-I.

The autonomic nervous system plays an important role in the regulation of body processes in health and disease. Overfeeding and obesity (a disproportional increase of the fat mass of the body) are often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The overfeeding-induced changes in autonomic outflow occur with typical symptoms such as adiposity and hyperinsulinemia. There might be a causal relationship between autonomic disturbances and the consequences of overfeeding and obesity. Therefore studies were designed to investigate autonomic functioning in experimentally and genetically hyperphagic rats. Special emphasis was given to the processes that are involved in the regulation of peripheral energy substrate homeostasis. The data revealed that overfeeding is accompanied by increased parasympathetic outflow. Typical indices of vagal activity (such as the cephalic insulin release during food ingestion) were increased in all our rat models for hyperphagia. Overfeeding was also accompanied by increased sympathetic tone, reflected by enhanced baseline plasma norepinephrine (NE) levels in both VMH-lesioned animals and rats rendered obese by hyperalimentation. Plasma levels of NE during exercise were, however, reduced in these two groups of animals. This diminished increase in the exercise-induced NE outflow could be normalized by prior food deprivation. It was concluded from these experiments that overfeeding is associated with increased parasympathetic and sympathetic tone. In models for hyperphagia that display a continuously elevated nutrient intake such as the VMH-lesioned and the overfed rat, this increased sympathetic tone was accompanied by a diminished NE response to exercise. This attenuated outflow of NE was directly related to the size of the fat reserves, indicating that the feedback mechanism from the periphery to the central nervous system is altered in the overfed state.

In higher vertebrates, two opposite behavioral coping strategies can be distinguished that are associated by a typical neuroendocrine pattern. Little is known about the individual variation in the stress response in lower vertebrates such as teleosts. In the present study, rainbow trout were fitted with an indwelling aortic catheter for repeated blood sampling and exposed to severe hypoxia and subsequent recovery and their behavior was characterized semiquantitatively during hypoxia. Blood levels of catecholamines, cortisol, glucose, FFA, lactate, and electrolytes were measured. About 60% of the fish survived the experiment whereas the others died during the recovery period. Behavioral strategy appeared to be highly related to survival since nonsurviving fish displayed strenuous avoidance behavior involving burst type activity whereas surviving fish did not panic and remained quiet. These behavioral differences were associated with marked differences in plasma catecholamine levels, which were 4- to 5-fold higher in nonsurviving fish as compared to survivors whereas the cortisol response tends to be lower in nonsurviving fish. Plasma lactate levels in nonsurvivors were 4- to 5-fold higher as compared to survivors while a severe hyperkalemia developed during recovery indicating the loss of intracellular homeostasis. The individual differences in behavioral concepts and neuroendocrine activation observed in rainbow trout during stress show great similarity with the active and passive coping strategies distinguished in higher vertebrates and may be determinant for survival during hypoxia.

Grafted islets become denervated due to the islet transplantation procedure. The aim of the present study was 1) to examine whether islet grafts in the liver, the spleen, and under the kidney capsule in rats become reinnervated following the transplantation and experimental procedures used in our laboratory, 2) whether there is any difference in reinnervation at these different sites, and 3) how these results relate to previous physiological experiments. Isogeneic isolated islets were transplanted into diabetic Albino Oxford rats, resulting in normoglycaemia. After at least 5 wk, graft-receiving organs were removed and several antibodies were employed to detect insulin, neuron-specific proteins, and cholinergic and noradrenergic nerve fibers. Islets in all three receiving organs contained viable insulin-positive B-cells. Neuron-specific enolase (NSE) as well as the growth-associated protein B-50 was observed at all sites. The cholinergic marker choline acetyltransferase (ChAT) was localized in islets grafts at all sites, but with the lowest density in the spleen. Staining for the noradrenergic markers tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) was observed in islet grafts at all sites with the lowest density in grafts under the kidney capsule. All these neurochemical substances were most frequently observed in fibers associated with blood vessels, which may be the route along which nerves grow into the graft. It can be concluded that 1) islet grafts in the liver, in the spleen and under the kidney capsule become reinnervated; 2) the innervation pattern of the islet grafts differs only slightly from that in the control pancreatic islets; and 3) in combination with our previously physiological data, we can conclude that these nerve fibers are, at least partly, functionally active.

Obesity is known as a risk factor in stress-related cardiovascular pathology in man. The length of obesity can be an important interacting variable. Therefore, cardiac and behavioral responses to emotional stress were studied in 1-year-old, genetically obese (fa/fa) and lean(Fa/-) male Zucker rats, a frequently used animal of genetic obesity. An early bradycardic response to emotional stress evoked by stimuli associated with brief previous inescapable foot shock, as observed in lean rats, was absent in the fatty Zuckers. This difference was not due to a learning deficit: obese and lean Zuckers showed the same degree of conditioned behavioral responses to the emotional stress. Furthermore, the magnitude of the novelty induced behavioral arousal was also comparable. As far as the regulation of body temperature is concerned, the fa/fa rats displayed a diminished increment in rectal temperature in response to the emotional stress. In conclusion, the results showed an impairment of phasic change in the parasympathetic drive of heart to emotional stress in the long-term obese animals. The diminished activation of heat production points to a blunted response of certain branches of the sympathetic nervous system to emotional stress. The findings favor the hypothesis that dysfunction of cardiac vagal drive in relation to stress is of pathologic importance in long-term obesity.

Obesity is often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The present paper summarizes the results of a number of studies designed to investigate autonomic functioning in normal, genetically, and experimentally obese rats. Particular emphasis is given to autonomic functioning and dysfunctioning in relation to the processes that are involved in the regulation of peripheral energy substrate homeostasis. It is concluded that alterations in autonomic regulation in obesity are determined by causal factors such as overeating, genetic make-up, age and/or the duration of obesity.

The influence of 48 hours of starvation on sympathoadrenal regulation of nutrient utilization was investigated in rats. To assess the role of alpha- and beta-adrenoceptors, rats were studied during alpha- and beta-blockade. Energy metabolism was measured using indirect calorimetry before, during, and after moderate swimming exercise (approximately 60% maximal O2 consumption [VO2max]). Additionally, blood samples were taken for determination of nutrient and hormone concentrations. In 48-hour-starved rats, under baseline conditions, there was a reduction in energy expenditure (EE) accompanied by a shift toward fat oxidation (fat-ox) in comparison to fed rats. Exercise-induced responses in EE, fat-ox, and carbohydrate oxidation (CHO-ox) did not differ from those in fed rats. In starved rats, a stronger response to exercise of the sympathoadrenal system was observed. In comparison to control 48-hour-starved rats, blockade of alpha- and beta-adrenoceptors led to a reduction in the exercise-induced increase in EE and fat-ox. The rate of CHO-ox was slightly reduced after blockade of either adrenoceptor type. Alpha-blockade prevented the exercise-induced increase in blood glucose. Plasma free fatty acid (FFA) was not affected. Blood lactate, plasma insulin, norepinephrine (NOR), and epinephrine (EPI) were increased after alpha-blockade. Due to beta-blockade, exercise-induced increases in glucose and FFA were prevented. Blood glucose even declined below the baseline value. EPI showed an exaggerated increase, and NOR showed a smaller increase. Results obtained in starved rats support the idea that alpha-adrenoceptor blockade-induced changes in energy metabolism are the result of a diminished oxygen supply due to diminished circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Transplantation of islets of Langerhans in diabetic rats normalizes resting glucose and insulin levels, but it remains unclear whether islet transplantation restores resting and exercise-induced energy metabolism. Therefore, we compared energy metabolism in islet transplanted rats with energy metabolism in normal controls and in streptozotocin-induced diabetic rats. Indirect calorimetry was applied before, during, and after moderate swimming exercise. Blood was sampled by means of a heart catheter for determination of nutrient and hormone concentrations. In islet transplanted rats, the results from indirect calorimetry and the nutrient and hormone concentrations were similar to the results in normal controls. In resting diabetic rats, insulin levels were very low, while glucose levels were exaggerated. Compared to resting controls, fat oxidation and energy expenditure were elevated, but carbohydrate oxidation was similar. Exercise increased energy expenditure and was similar in diabetic and control rats. Carbohydrate oxidation was lower and fat oxidation was higher in diabetic than in control rats. Exercise-induced increments in glucose, lactate and non-esterified fatty acid levels were the highest in diabetic rats. Thus, at rest, but not during exercise, insulin influences energy expenditure. Insulin reduces lipolysis and glycogenolysis. It enhances the relative contribution of carbohydrate oxidation and reduces fat oxidation to total energy expenditure, at rest and during exercise. Absence of insulin enhances anaerobic glycolytic pathways during exercise. It is concluded that in diabetic rats, islet transplantation of 50% of the normal pancreatic endocrine volume successfully normalizes insulin levels and hence energy metabolism at rest and during exercise.

The truncated glucagon-like peptide-1 (GLP-1(7-36)amide or GLP-1) stimulates insulin secretion, enhances glucose elimination and is of potential interest in diabetes treatment. We studied the hypoglycemic action of GLP-1 in normal mice when given alone or together with the fructose analogue, 2,5-anhydro-D-mannitol (2,5-AM), which inhibits glycogenolysis and gluconeogenesis. GLP-1 (32 nmol/kg iv) lowered plasma glucose levels after 25 min to 4.6 +/- 0.2 mmol/l compared with 7.3 +/- 0.4 mmol/l in controls (P < 0.001). Also 2,5-AM (0.5 mumol/kg iv) reduced plasma glucose levels, to 5.6 +/- 0.3 mmol/l (P < 0.01). When given together, the glucose lowering action of GLP-1 and 2,5-AM was additive, since the 25 min glucose level was 2.8 +/- 0.2 mmol/l. At 5 min after injection, GLP-1 had increased plasma insulin levels to 693 +/- 68 pmol/l compared with 342 +/- 42 pmol/l in controls (P < 0.01). 2,5-AM abolished this increase. Furthermore, GLP-1 (32 nmol/kg) did not affect the glycogen content, neither in the liver nor in the gastrocnemic muscle in samples taken at 30 min after injection. Moreover, in isolated islets incubated at 3.3 and 8.3 mmol/l glucose, 2,5-AM at 75 mmol/l inhibited glucose-stimulated insulin secretion (P < 0.05) showing that 2,5-AM inhibits insulin secretion both in vivo and in vitro. We conclude that GLP-1 may reduce plasma glucose levels also to levels below the basal levels under normal conditions, and that an insulin- and liver-independent action of the peptide contributes to its hypoglycemic action in normal animals.

Neuroglycopenia induced by administration of 2-deoxy-D-glucose is known to stimulate the secretion of both insulin and glucagon in mice by a mechanism that is dependent on neural activity. In the present study, we examined whether the neurotransmitter nitric oxide (NO) is involved in this process. Therefore, 2-deoxy-D-glucose (500 mg/kg) was injected intravenously alone or together with the inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (50 mg/kg) to conscious mice. It was found that NG-nitro-L-arginine methyl ester inhibited the increased plasma levels of both insulin (by 26%; P = 0.039) and glucagon (by 45%; P < 0.001) at 10 min after injection of 2-deoxy-D-glucose. Similarly, the NO synthase inhibitor, NG-nitro-L-arginine, which is devoid of the anticholinergic property of NG-nitro-L-arginine methyl ester, inhibited the responses of both insulin (by 53%; P = 0.026) and glucagon (by 57%; P = 0.003) to 2-deoxy-D-glucose. In contrast, the stereoisomer of NG-nitro-L-arginine methyl ester, NG-nitro-D-arginine methyl ester, which is devoid of NO synthase inhibitory activity, was without effect on 2-deoxy-D-glucose-induced insulin and glucagon secretion. Plasma levels of adrenaline and noradrenaline after administration of 2-deoxy-D-glucose were also reduced by NG-nitro-L-arginine methyl ester. In contrast, the insulin and glucagon secretory responses to intravenous injection of arginine (250 mg/kg), glucose (500 mg/kg) or the cholinergic agonist, carbachol (30 micrograms/kg), were not influenced by NG-nitro-L-arginine methyl ester, NG-nitro-D-arginine methyl ester or NG-nitro-L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to investigate the mechanism leading to inhibition of insulin release during exercise. To investigate the influence of circulating epinephrine and norepinephrine, these catecholamines were infused intravenously in resting islet-transplanted and control rats. The role of neural influences on insulin release was investigated by a swimming exercise study in islet-transplanted and control rats, before and after adrenodemedullation. Streptozotocin-induced diabetic Albino Oxford rats received 5 microliters islet tissue into the portal vein, resulting in return of normal basal glucose and insulin levels. Transplanted and control animals were provided with two permanent heart catheters to sample blood and to give infusions. Infusion of epinephrine and norepinephrine did not result in inhibition of plasma insulin levels. Blood glucose levels, as well as nonesterified fatty acids and insulin levels in plasma, were similar in both groups. After the infusion study, the animals were subjected to strenuous swimming. During exercise, plasma insulin levels decreased not only in controls, but also in the islet-transplanted group. Blood glucose and plasma catecholamine responses were identical in both groups. After adrenodemedullation, epinephrine was not detectable and the exercise-induced decrease of insulin was not affected. These results indicate that circulating epinephrine and norepinephrine in physiological concentrations do not cause inhibition of insulin secretion. Since the exercise-induced inhibition of insulin secretion is still present in rats with islet grafts, it seems reasonable to suggest that sympathetic neural influences are responsible for the inhibition of insulin release during exercise and that transplanted islets are sympathetically reinnervated.

Common carp (Cyprinus carpio L.), kept at 20 degrees C, were fitted with an indwelling PE-50 cannula in the dorsal aorta. Hormones dissolved in Ringer saline were arterially infused at a rate of 1 microgram.kg-1.min-1 for epinephrine (Epi), 2 micrograms.kg-1.min-1 for norepinephrine (NE), and 1.33 micrograms.kg-1.min-1 for insulin. INfusion of bovine insulin in carp resulted in a long lasting (24 h) decrease of plasma free fatty acids (FFA; -0.41 +/- 0.06 mM) and glucose levels (-3.14 +/- 0.25 mM) compared with preinfusion levels at t = 0. Both Epi and NE induced a marked hyperglycemia although Epi was more potent (+8.2 +/- 0.9 and +6.9 +/- 0.8 mM, respectively). Plasma FFA levels increased by 0.25 +/- 0.03 mM compared with preinfusion levels on Epi infusion. In contrast, during NE infusion, plasma FFA levels decreased significantly by -0.21 +/- 0.03 mM. Plasma insulin titers did not significantly change during infusion of NE or Epi. It is concluded that the ratio of NE to Epi is the major factor that determines the effect of catecholamines on plasma FFA levels in carp. These results may explain species-dependent different effects of hypoxia on FFA metabolism in fish.

alpha- and beta-adrenoceptors play a key role in the regulation of nutrient supply to working muscles during exercise. To assess their influence in the regulation of substrate utilization, rats were studied during alpha- or beta-adrenoceptor blockade. Energy metabolism was studied by means of indirect calorimetry before, during, and after moderate swimming exercise. Blood samples were taken for the determination of nutrient and hormone concentrations. In addition, central venous blood samples were withdrawn for determination of blood gases, pH, and total hemoglobin concentration (c/Hb). alpha- and beta-adrenoceptor blockade decreased the rates of energy expenditure (EE) and fat oxidation (fat-ox) during and after swimming in comparison to swimming without adrenoceptor blockade. The oxidation of carbohydrates (CHO-ox) was increased in both cases. alpha-Blockade prevented the exercise-induced increase in blood glucose, plasma free fatty acids (FFA) were not affected, and plasma insulin, norepinephrine (NOR), epinephrine (EPI), and lactate were markedly increased. beta-adrenoceptor blockade prevented the exercise-induced increases in blood glucose and FFA. EPI increased slightly more than and NOR less than in the control experiment. The exercise-induced decrease in insulin was more pronounced after beta-blockade. alpha-Blockade caused a less pronounced decrease in venous oxygen saturation (SO2) and tension (PO2) than in the control experiment. The exercise-induced increase in carbon dioxide tension (PCO2) was almost absent. After beta-blockade, venous SO2 and PO2 decreased more and PCO2 increased more than in the control experiment. It is concluded that both alpha and beta-blockade restrict the rate of EE during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Activity in sympathetic liver nerves has been proposed to be important for glucose production in exercising humans. However, liver denervation does not influence the exercise-induced increase in glucose production in the rat and dog. These species have a poor sympathetic liver innervation in contrast to the rich innervation in humans. The effect of liver denervation on glucose production during exercise was therefore studied in the guinea pig, a species with a rich sympathetic hepatic innervation comparable to that of humans. Guinea pigs were selectively liver denervated (n = 9) or sham operated (n = 8) and instrumented with a carotid and a jugular catheter. One week later they ran on a treadmill at 32 m/min for 20 min. Glucose turnover was evaluated by a primed constant-rate intravenous infusion of [3-3H]glucose. Arterial blood was sampled for analysis of hormones and metabolites. At rest, liver-denervated guinea pigs had lower glucose turnover and plasma concentrations of glucose, glycerol, and cortisol than control animals. During running, the increase in hepatic glucose production was similar in the two groups (4.1 +/- 0.8 vs. 3.8 +/- 0.7 mumol.min-1.100 g-1 in control animals) and so were hepatic (247 +/- 25 vs. 246 +/- 45 mmol glucose units/kg wet wt in control animals) and muscle glycogen concentrations at the end of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the regulation of autonomic outflow, hormonal (plasma insulin and catecholamines), metabolic (blood glucose and plasma free fatty acids) and cardiovascular (heart rate and main arterial pressure) indices were measured before, during, and after bilateral infusion of NPY (1.0, 0.2, 0.04 micrograms in 1 microliter synthetic CSF) into the PVN of conscious resting rats. Administration of the highest dose (1.0 microgram/microliter) caused bradycardia and reduced circulating norepinephrine levels without effecting circulating fuels, insulin or epinephrine. In a second experiment, feeding-induced changes in hormonal and metabolic indices were assessed after NPY administration (1.0 microgram/microliter) into the PVN. During and after feeding, NPY enhanced the feeding-induced insulin response (P < 0.01) and attenuated the feeding-induced norepinephrine response (P < 0.05). The results of the present study suggest that stimulation of NPY receptors in the PVN decreases sympathetic activity and increases parasympathetic activity in resting conditions, and that these effects are potentiated during feeding.

The impact of sensory nerves in glucose-stimulated insulin secretion and glucose tolerance was investigated in conscious mice treated neonatally with either capsaicin (Cap) or vehicle (Veh). At 10-12 wk after Cap, both the early (1 min) insulin secretory response to intravenous glucose (2.8 mmol/kg) (by 67%) and glucose elimination were potentiated (P < 0.05). In contrast, basal insulin, glucagon, and glucose were not affected by Cap. Plasma norepinephrine and epinephrine levels did not differ between Cap- and Veh-treated animals, whereas the increase in plasma insulin levels normally induced by alpha-adrenoceptor blockade by phentolamine was absent after Cap treatment. In isolated islets, the insulin secretory response to glucose (20 mmol/l), carbachol (0.1 mmol/l), or phentolamine (0.5 mmol/l) was not affected after Cap. It is concluded that sensory denervation by Cap results in increased glucose tolerance, which is in part because of a potentiated early insulin response to glucose. This potentiation does not seem secondary to altered plasma catecholamine levels or to altered islet secretory capacity. The results suggest rather that Cap-sensitive nerves, by a local effector function and/or as the afferent loop of a neural reflex, exert inhibitory influences on insulin secretion.

Monosodium glutamate (MSG) is used as a food additive to improve the taste of food. The effect of MSG on sweet taste is enhanced by guanosine 5'-monophosphate (GMP). Because increased palatability is known to increase the vagally mediated preabsorptive insulin response (PIR), we hypothesized that MSG and GMP will enhance the PIR. To study this, male Wistar rats were provided with permanent cannulas for venous blood sampling and intragastric drug administration. The MSG and GMP were either added to a test meal or infused into the stomach during a test meal. Blood samples were taken to measure concentrations of glucose, insulin, epinephrine (E), and norepinephrine (NE). Addition of 56 mg MSG to a control meal markedly reduced both phases of the meal-induced increase in plasma insulin and had no effects on blood glucose and plasma E and NE responses. Infusion of 56 mg MSG into the stomach at the onset of food intake reduced the PIR with no effect on glucose, E, NE, or the second phase insulin release. Addition of 2 mg MSG in combination with GMP to the test meal or gastric administration of these drugs did not affect the changes in any of the blood components measured. It is concluded that addition of a high dose of MSG to a test meal leads to a reduction in the vagal response to food.

A measuring system is described for the determination of oxygen consumption (Vo2) and carbon dioxide production (Vco2) in swimming rats. Vo2 and Vco2 were measured by means of an O2-analyzer (Ametek S3A) and a mass spectrometer (Balzers QMG 511), respectively, combined with a gas flow meter. The measurements were made in a 5-1 metabolic chamber on top of a swimming pool in which a water flow of 0.22 m/s was maintained. The rats were fitted with an indwelling catheter with its tip at the entrance of the right atrium for the repeated determination of energy substrate and hormone concentrations, before, during, and after swimming. The inaccuracy of the Vo2 and Vco2 measurements was 0.18% and 0.31% of the reading, respectively; the imprecision was 2.15% and 2.59%. This high accuracy and precision of the system was attained by measuring room air for 20 s after each 100 s of measuring air from the metabolic chamber, and by using demineralized water in the swimming pool. Vo2 during steady-state swimming was 1.89 +/- 0.06 mmol/kg.min (ca. 60% Vo2max), indicating moderate exercise. Respiratory quotient (RQ), during steady-state exercise, was 0.80 +/- 0.01. Vo2 and RQ resulted in rates for carbohydrate and fat utilization of 15.6 +/- 0.8 and 15.1 +/- 0.7 mg/kg.min, respectively.

The ventromedial and posterior hypothalamic nuclei are known to influence glucoregulation during exercise. The extensive projections of the paraventricular hypothalamic nucleus (PVN) to the sympathetic nervous system suggest that the PVN also may be involved in glucoregulation during exercise. The region of the PVN was anaesthetized with bupivacaine before running (26 m min-1) or continued rest, via previously implanted bilateral brain cannulas aimed at the dorsal aspect of the PVN. Control rats were treated identically to PVN-anaesthetized rats, but were not infused. Blood, for determination of plasma concentrations of metabolites and hormones, was drawn from a tail artery, and 3H-glucose was infused in a tail vein for glucose turnover determinations. At rest, no significant changes in plasma concentrations of metabolites or hormones were induced by anaesthesia of the region of the PVN. During exercise, glucose production and utilization and plasma concentrations of glucose, lactate, glycerol, noradrenaline, adrenaline, corticosterone, and glucagon increased (P < 0.02) and plasma insulin decreased (P < 0.02) in all rats. However, initially in exercise, adrenaline (4.3 +/- 0.8 vs. 7.9 +/- 1.0 nmol l-1 in controls, P < 0.05, t = 6 min) and later corticosterone levels (1.37 +/- 0.06 vs. 1.69 +/- 0.10 nmol l-1 in controls, P < 0.05, t = 20 min) were attenuated by PVN anaesthesia. Initially during exercise, glucose utilization was higher and plasma glucose lower in PVN-anaesthetized rats compared to controls (16.6 +/- 0.8 vs. 12.7 +/- 0.6 mumol min-1 100 g-1 and 7.1 +/- 0.2 vs. 8.1 +/- 0.2 mmol l-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The contribution of hepatic sympathetic innervation, glucagon and adrenaline to the glycaemic response to exercise was investigated in rats. Hepatically denervated (LDX) or sham operated (SHAM) rats with permanent catheters were therefore submitted to swimming with or without infusion of somatostatin in combination with adrenodemedullation. Blood samples were taken for measurements of blood glucose, plasma free fatty acids (FFA), adrenaline (A), noradrenaline (NA), insulin and glucagon. Liver denervation by itself did not influence glucose levels during exercise. Infusion of somatostatin in SHAM animals, which inhibited the exercise-induced glucagon response, led to enhanced sympathoadrenal outflow (measured as plasma A and NA) and a reduced blood glucose during exercise, suggesting that glucagon serves as a powerful mediator of the glycaemic response during swimming. Infusion of somatostatin in LDX animals failed to enhance plasma NA levels and led to a more pronounced reduction in blood glucose levels. This indicates that liver nerves do contribute to the glycaemic response to exercise when glucagon secretion is suppressed. Reduced blood glucose levels after adrenodemedullation revealed that adrenal A is another important mediator of the glucose response to exercise. Infusion of somatostatin in adrenodemedullated SHAM or LDX animals was not accompanied with increased NA outflow, suggesting that adrenal A is necessary to allow the compensatory increased outflow of NA from sympathetic nerves. In conclusion, the study shows that pancreatic glucagon and adrenal A are the predominant factors influencing the glycaemic response to exercise, whereas a role of the sympathetic liver nerves becomes evident when glucagon secretion is suppressed.

Blood-borne metabolic feedback vs. neural feedforward regulation of glucose homeostasis during exercise was investigated by infusion glucose and [3H]glucose for glucose appearance determination intravenously in rats running for 20 min at 28 m/min [approximately 85% of maximal O2 consumption (VO2max)]. Infused glucose corresponded to the exercise-induced increase in hepatic glucose production (HGP) found in saline-infused rats. Saline- and glucose-infused resting rats were also studied. Arterial blood was sampled for analyses of hormones and metabolites. Plasma epinephrine, norepinephrine, and insulin were always similar and HGP was initially similar in the two exercising groups, although glucose infusion resulted in higher plasma glucose compared with control (P < 0.05). Late during exercise, high plasma glucose (11.3 +/- 0.4 vs. 9.6 +/- 0.3 mM) and low glucagon (16 +/- 2 vs. 27 +/- 3 pM) in glucose- vs. saline-infused rats caused an inhibition of HGP in glucose-infused rats, although never below preexercise levels. In resting rats, glucose infusion resulted in elevated plasma glucose and insulin and, in turn, inhibition of HGP but had no effect on catecholamines, corticosterone, or glucagon. The findings indicate that during heavy exercise, glucose homeostasis is regulated primarily by neural feedforward mechanisms and that blood-borne metabolic feedback mechanisms play a regulatory role if metabolic error signals are pronounced.

The metabolic consequences of the development of obesity and the underlying mechanisms were investigated. For this purpose, male rats were overfed for 5 weeks through long-term gastric catheters. Permanent cardiac cannulas implanted before the overfeeding period allowed frequent blood sampling and infusions without disturbing the rats. Hyperalimented rats became grossly obese, displayed elevated basal plasma norepinephrine (NE) concentrations, and developed hyperinsulinemia and insulin insensitivity, but remained normoglycemic and preserved normal intravenous (IV) glucose tolerance. During physical exercise (ie, 15 minutes of swimming), obese rats displayed exaggerated increases in blood glucose concentrations, whereas plasma free fatty acid (FFA) responses were blunted. These alterations were probably due to decreased NE release by the sympathetic nervous system during exercise and to altered tissue responsivity to adrenergic stimulation. The latter was demonstrated by infusions of catecholamines in the resting state. Responses to mild stress were increased in obese animals, as indicated by increased responses of plasma epinephrine (E) and corticosterone during handling and first contact with water. The results of the present study indicate that overfeeding induces changes in the sympathetic control of metabolism and insulin secretion. Whereas elevated NE levels in the basal state probably reflect increased energy expenditure, the pattern of nutrient mobilization during exercise is directed toward sparing of fats.

Exercise is known to increase hepatic glucose production. Previous studies have suggested that the sympathetic nerves only marginally contribute to this process. This study examined whether increased catecholamine response or increased adrenoceptor sensitivity might have affected previous results showing no effect of hepatic denervation on the increased hepatic glucose production during exercise. Hepatic sympathetic denervated rats, sham-operated rats and control rats were forced to swim against a counter current for 15 minutes. Denervations and sham operations were performed 9 days prior to swimming. The results show that denervation did not affect the changes in levels of blood glucose, plasma FFA, and catecholamines before, during and after swimming. Furthermore, hepatic adrenoceptor sensitivity was not altered in denervated rats, since intravenous infusions of epinephrine (20 ng/min) and norepinephrine (50 ng/min) similarly changed blood glucose and plasma FFA levels in liver-denervated, sham-operated and control rats. Thus, the increase in blood glucose levels during intravenous infusion of epinephrine and norepinephrine in the respective groups was 1.2 +/- 0.3 and 1.0 +/- 0.3 mmol/l (liver-denervated rats), 1.6 +/- 0.4 and 0.7 +/- 0.3 mmol/l (sham-operated rats) and 1.3 +/- 0.3 and 0.8 +/- 0.3 mmol/l (control rats), respectively. After adrenodemedullation, however, the rise of glucose levels during swimming in liver-denervated and control rats was completely abolished. Thus, the glucose response to swimming with and without adrenodemullation was 0.1 +/- 0.4 and 1.7 +/- 0.4 mmol/l in liver-denervated rats (P < 0.01) and -0.2 +/- 0.4 and 2.2 +/- 0.2 mmol/l in control rats (P < 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intrahypothalamic administration of norfenfluramine (NFFL), an anorectic agent that increases serotonergic transmission, on plasma concentrations of glucose, free fatty acids (FFA), and their regulating hormones were investigated in resting and exercising rats. Infusion of 5 micrograms NFFL in 0.125 microliter aCSF/min into the nucleus paraventricularis of the hypothalamus (PVN) caused a significant increase of blood glucose, plasma epinephrine (E), and corticosterone concentrations. Plasma levels of FFA, insulin, or norepinephrine (NE) remained unchanged. Lower doses of NFFL (0.5 and 0.05 microgram/min) did not affect peripheral metabolism. The effects of NFFL in the PVN were completely prevented by prior administration of a 5-HT1 antagonist, (S)-(-)propranolol. The exercise-induced increase of plasma NE was reduced after prior administration of 5 micrograms NFFL/min into the PVN. Plasma E responses tended to be increased. The exercise-induced alterations in glucose, FFA, corticosterone, and insulin were not affected by NFFL infusion into the PVN. The data suggest that activation of serotonergic mechanisms in the PVN might change the neurohormonal response to a stressor favouring the release of adrenal hormones above activation of the neuronal branch of the sympathetic nervous system.

The effect of chronic intragastric administration of dexfenfluramine (FFL, 1 mg/kg, twice a day), a drug that increases serotonergic transmission, on peripheral energy substrate metabolism was investigated. Rats were provided with permanent cannulas, allowing stress-free intragastric treatment and blood sampling. Fenfluramine-treated and control animals were submitted to strenuous swimming at days -2, 1, 4, and 7 relative to the onset of FFL treatment at day 0. Blood samples were taken before, during, and after exercise. Thereafter, possible changes in catecholamine sensitivity were investigated during intravenous infusions of norepinephrine (NE) and epinephrine. Finally, energy expenditure, including resting respiratory quotient (RQ), and carbohydrate and fat utilization were measured under baseline conditions. It was found that chronic administration of FFL led to a transient reduction in the exercise-induced increase of blood glucose concentrations. Plasma norepinephrine responses to exercise gradually increased in the FFL-treated animals. Baseline RQ was markedly increased in the FFL-treated animals, indicating an increase of carbohydrate utilization and a decrease of fat combustion. Total energy expenditure remained unchanged. The increased RQ was accompanied by increased sensitivity for NE and significantly decreased baseline concentrations of plasma free fatty acids.

The effects of chronic intragastric administration of the anorectic agent d-fenfluramine on energy metabolism and nutrient concentrations were investigated at rest and during swimming. Rats were provided with permanent cannulas for blood sampling and intragastric administration of d-fenfluramine or saline. Energy expenditure and nutrient and hormone concentrations were determined. Under baseline conditions, d-fenfluramine increased carbohydrate utilization (14.2 vs. 7.0 mg/kg.min) and decreased fat oxidation (2.8 vs. 5.5 mg/kg.min). Plasma free fatty acid concentration was decreased (0.29 vs. 0.55 mmol/l) and lactate and insulin concentrations were increased after d-fenfluramine treatment (0.64 vs. 0.37 mmol/l and 61 vs. 33 mU/l, respectively). The shift in nutrient utilization also occurred during swimming. The exercise-induced increase in blood glucose was reduced after d-fenfluramine (+0.8 vs. +2.0 mmol/l). During swimming, free fatty acid, lactate and insulin concentrations were similar in the two groups. It is hypothesized that chronic d-fenfluramine treatment increases in the oxidation of carbohydrates and decreases the oxidation of fat as a result of a decrease in the transport of fatty acids over the mitochondrial membrane.

The effects of genetic obesity on the actions and alterations of the sympathetic nervous system were studied in 10-12-month-old obese (fa/fa) and lean (Fa/-) Zucker rats. Blood glucose, plasma insulin, epinephrine (E), norepinephrine (NE), and free fatty acids (FFA) concentrations were measured in blood samples taken through a permanent heart catheter before, during, and after exercise or intravenous infusion of E and NE. Baseline plasma FFA and insulin levels were markedly increased in the obese animals. Exercise, i.e., strenuous swimming against a counter current for 15 min, led to reduction of plasma insulin concentrations and an increase of all other blood components in lean Zucker rats. In obese animals, an exaggerated increase of blood glucose and a large suppression of plasma insulin occurred. Plasma FFA levels tended to decline during exercise. Plasma catecholamine patterns in the exercising fatty Zuckers were not different to those of the lean animals. Infusion of E caused an increase of blood glucose and a decrease of plasma insulin concentrations in both groups of animals. The increase in blood glucose in the obese animals was significantly larger compared to the changes in the lean animals. Infusion of NE significantly reduced plasma insulin concentration in obese but not in lean animals. The results revealed that activation of the sympathetic system, expressed as exercise-induced alterations in plasma E and NE levels, is normal in obese Zucker rats. However, postsynaptic receptor effects of catecholamines on glycogenolysis and lipolysis are different in obese and lean animals, which points to permanent changes in adrenoceptor mechanisms on adipocytes, hepatocytes, and muscle cells in obesity.