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Biomedical subjects

A J Scheurink

Publications and source records attributed to A J Scheurink.

At least 19 recordsLinked to original sources
PubMed2001

Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats.

The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake-independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i.e., corticotropin-releasing hormone (CRH), cocaine-amphetamine-related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle-treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight ( approximately 14%) and fat content ( approximately 90%), hepatic glycogen content ( approximately 40%), and plasma levels of cholesterol ( approximately 48%), insulin ( approximately 259%), glucagon ( approximately 80%), and leptin ( approximately 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair-feeding of i3vt SHU9119-treated animals to i3vt vehicle-treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol ( approximately 31%) and leptin ( approximately 104%) and body fat content ( approximately 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i.e., CART, POMC, and NPY) and paraventricular (i.e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake-dependent and -independent mechanisms.

Animals↗
PubMed2000

Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation.

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.

Animals↗
PubMed2000

NPY-leptin: opposing effects on appetitive and consummatory ingestive behavior and sexual behavior.

Many studies have indicated that neuropeptide Y (NPY) stimulates and leptin inhibits food intake. In line with this, intracerebroventricular injection of NPY (10 microg) stimulated and leptin (10 microg) inhibited intake of a sucrose solution when female rats were required to obtain the solution from a bottle. However, NPY inhibited and leptin stimulated intake if the solution was infused intraorally. Thus NPY stimulates the responses used to obtain food but inhibits those used to consume food, and leptin has the opposite effects. To test the specificity of these responses the sexual behavior of male rats was examined. NPY-treated males showed minor deficits in sexual behavior but chose to ingest a sucrose solution rather than copulate with a female if offered the choice. By contrast, leptin-treated males ingested little sucrose and displayed an increase in ejaculatory frequency if given the same choice. It is suggested that NPY is not merely an orexigenic peptide, but one that directs attention toward food. Similarly, leptin may not be an anorexic peptide, but one that diverts attention away from food toward alternate stimuli.

Administration, Oral↗
PubMed1999

Exercise and the regulation of energy intake.

Energy balance is the resultant of ingested calories and energy expenditure and is generally maintained within narrow limits over prolonged periods. Exercise leads to an increase in energy expenditure which is, in the long-term, counteracted by increased energy intake. Evidence for this comes from a study in voluntarily running female rats that increased their daily food intake to 130% of the sedentary controls. In contrast, when considered on a short-term basis, exercise will suppress food intake to prevent a potentially dangerous disruption of energy substrate homeostasis. Studies in permanently cannulated rats submitted to a test meal and 2 hrs swimming reveal that both food intake and exercise lead to increases in glucose and free fatty acid (FFA) levels in the blood. These changes in glucose and FFA, combined with the exercise-induced alteration in among others glucagon, corticotropin releasing hormone (CRH) and body temperature, may lead to the short-term anorexic effect of exercise.

Animals↗
PubMed1998

PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice.

Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-stimulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1-5 min) insulin response was 3.8 +/- 0.4 nmol/l (PACAP-27) and 3.3 +/- 0.3 nmol/l (PACAP-38), respectively, vs. 1.4 +/- 0.1 nmol/l after glucose alone (P < 0.001), and the total area under the curve for insulin (AUCinsulin) was potentiated by 60% (P < 0.001). In contrast, PACAP-27 and PACAP-38 reduced the insulin sensitivity index (SI) [0.23 +/- 0.04 10(-4) min-1/(pmol/l) for PACAP-27 and 0.29 +/- 0.06 10(-4) min-1/(pmol/l) for PACAP-38 vs. 0.46 +/- 0.02 10(-4) min-1/(pmol/l) for controls (P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUCinsulin times SI) were not affected by PACAP-27 or PACAP-38. Finally, when given together with glucose, PACAP-27 did not alter plasma glucagon or norepinephrine levels but significantly increased plasma epinephrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the latter possibly explained by increased epinephrine. This complex action explains why the peptide does not enhance glucose disposal.

Animals↗
PubMed1998

Marked hyperleptinemia after high-fat diet associated with severe glucose intolerance in mice.

We asked whether the likelihood for mice of the C57BL/6J strain to develop glucose intolerance when fed a high-fat diet is related to the increase in circulating levels of leptin or free fatty acids (FFA). We therefore administered a high-fat diet (58% fat) or a control diet (11% fat) for 1.5 years. NMRI mice were used as a more glucose-tolerant control group. After a high-fat diet, the area under the glucose curve following an intraperitoneal glucose challenge (1 g/kg) increased more markedly in C57BL/6J mice (by 42+/-8%) than in NMRI mice (by 21+/-3%, P = 0.007). Plasma levels of insulin, leptin and FFA increased in both strains of mice, whereas plasma glucose levels were elevated after the high-fat diet only in C57BL/6J mice. The slope of the relationship between body weight and plasma leptin was higher in C57BL/6J mice than in NMRI mice. suggesting leptin insensitivity. Circulating leptin correlated to circulating insulin in both strains of mice, whereas plasma FFA correlated to plasma insulin in NMRI mice but not in C57BL/6J mice. These correlations remained significant after adjustment for body weight. The results show that elevated leptin and FFA levels evolve after high-fat feeding in mice, in conjunction with evolvement of glucose intolerance and hyperglycemia.

Animals↗
PubMed1997

Dissociated insulinotropic sensitivity to glucose and carbachol in high-fat diet-induced insulin resistance in C57BL/6J mice.

To study islet function following reduced insulin sensitivity, we examined mice of the C57BL/6J strain, the genotype of which carries an increased propensity to develop insulin resistance when metabolically challenged. The mice received either a high-fat diet (58% fat on an energy basis) or a control diet (11% fat) for 12 weeks. The body weight of mice on the high-fat diet increased significantly more than that of mice on the control diet (25.8 +/- 0.4 v 21.3 +/- 0.2 g, P < .001). Already after 1 week on the high-fat diet, a significant hyperglycemia accompanied by hyperinsulinemia had evolved, indicative of insulin resistance. After 12 weeks, plasma glucose levels for high-fat diet-treated mice were 7.5 +/- 0.1 mmol/L, versus 6.5 +/- 0.1 mmol/L in controls (P < .001); corresponding values for plasma insulin were 248 +/- 17 and 104 +/- 7 pmol/L, respectively (P < .001). Mice given a high-fat diet also had elevated levels of total cholesterol, triglycerides, and free fatty acids (FFAs) compared with controls. After 4, 8, and 12 weeks, glucose (2.8, 8.3, or 16.7 mmol/kg) or the cholinergic agonist carbachol (0.16 or 0.53 micromol/kg) was injected intraperitoneally. The insulinotropic response to glucose was not different between the two groups after 4 or 8 weeks, whereas after 12 weeks, glucose-induced insulin secretion was markedly impaired in high-fat diet-treated mice (P < .001). In contrast, after 8 and 12 weeks on a high-fat diet, carbachol-stimulated insulin secretion was potentiated (P < .01), whereas carbachol-stimulated glucagon secretion was not significantly altered. Furthermore, after 12 weeks on the high-fat diet, insulin secretion from isolated islets was impaired at glucose levels of 8.3, 11.1, and 16.7 mmol/L (P < or = .05). Moreover, islet morphology as examined by immunocytochemistry using insulin antibodies and islet innervation, as revealed by immunostaining of tyrosine hydroxylase (TH), neuropeptide Y (NPY), galanin, vasoactive intestinal polypeptide (VIP), and substance P (SP) were unaffected by the high-fat diet for 12 weeks. However, quantitative in situ hybridization showed a 3.5-fold upregulation of insulin gene expression in response to the high-fat diet (P < .001) despite unaltered B-cell mass and pancreatic insulin content. We conclude that as little as 1 week of treatment with a high-fat diet induces insulin resistance in C57BL/6J mice. This is accompanied later by hyperlipemia, potentiated carbachol-stimulated insulin secretion, and increased insulin gene expression but impaired glucose-stimulated insulin secretion. We suggest that after several weeks' duration, insulin resistance is accompanied by enhanced islet sensitivity to cholinergic activation and exaggerated insulin gene expression, whereas the failing islet sensitivity to glucose represents decompensation.

Animals↗
PubMed1997

Central leptin stimulates corticosterone secretion at the onset of the dark phase.

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.

Analysis of Variance↗
PubMed1996

Overfeeding, autonomic regulation and metabolic consequences.

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.

Animals↗
PubMed1995

Involvement of nitric oxide in neuroglycopenia-induced insulin and glucagon secretion in the mouse.

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)

Animals↗
PubMed1995

Energy homeostasis, autonomic activity and 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.

Animals↗
PubMed1995

Effects of GLP-1 and 2,5-anhydro-D-mannitol on insulin secretion and plasma glucose in mice.

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.

Animals↗
PubMed1994

Effects of monosodium glutamate (umami taste) with and without guanosine 5'-monophosphate on rat autonomic responses to meals.

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.

Administration, Oral↗
PubMed1994

Contribution of liver nerves, glucagon, and adrenaline to the glycaemic response to exercise in rats.

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.

Adrenal Medulla↗
PubMed1994

Weight loss in rats following intraventricular transplants of pancreatic islets.

Because of the body's resistance to permanent weight change, obesity remains a major health problem in modern society. It is hypothesized that the regulatory system defending body weight utilizes pancreatic insulin as an indicator of adiposity to the brain. To take advantage of this negative feedback system, we transplanted neonatal (experiment 1) or adult (experiment 2) pancreatic islets containing insulin-secreting cells into the 3rd ventricle of syngeneic Lewis rats. This resulted in an elevation of the insulin signal within the brain and a significant long-term reduction of body weight. Changes in food intake were consistent with the changes of body weight. The implantation of more islets resulted in a greater reduction of body weight, and changes in weight were inversely correlated with the level of insulin achieved in the cerebrospinal fluid. After the two studies were completed, histological examination revealed the presence of insulin-containing cells within the 3rd ventricle and adjacent hypothalamus. These studies suggest that transplanted insulin-secreting cells may provide a potential therapeutic strategy for maintenance of weight loss.

Animals↗
PubMed1994

Involvement of capsaicin-sensitive nerves in regulation of insulin secretion and glucose tolerance in conscious mice.

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.

Afferent Pathways↗