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R J Seeley

Publications and source records attributed to R J Seeley.

At least 37 records · Page 2Linked to original sources
PubMed2000

The role of CNS glucagon-like peptide-1 (7-36) amide receptors in mediating the visceral illness effects of lithium chloride.

Peripheral administration of large doses of lithium chloride (LiCl) to rats causes a spectrum of effects that are consistent with visceral illness. LiCl reduces food intake, decreases salt ingestion after sodium depletion, induces pica, and produces robust conditioned taste aversions. Because some of the effects of peripheral LiCl are mimicked by centrally administered glucagon-like peptide-1 (7-36) amide (GLP-1), we hypothesized that this peptide is involved in the neural pathways by which LiCl causes visceral illness. To test this hypothesis, we pretreated rats with a selective and potent GLP-1 receptor antagonist given directly into the third ventricle via an indwelling cannula before administration of peripheral LiCl. The GLP-1 receptor antagonist completely blocked the effect of LiCl to reduce food intake, induce pica, and produce a conditioned taste aversion. The same dose of GLP-1 receptor antagonist did not reverse the LiCl-induced reduction in NaCl intake. The data indicate a role for GLP-1 receptors in the CNS pathway that mediates some of the effects of visceral illness.

Angiotensins↗
PubMed2000

CNS melanocortin system involvement in the regulation of food intake.

Accumulating evidence indicates that the central melanocortin (MC) system plays a key role in the regulation of food intake and energy balance. This evidence includes findings that either spontaneous genetic mutations or targeted gene deletions that impair melanocortin signaling cause disrupted food intake and body-weight control. In addition, expression of the mRNA that encodes the endogenous agonists and antagonists for CNS melanocortin receptors is regulated by changes in energy balance and body-adiposity signals. Finally, administration of both natural and synthetic ligands to MC receptors produces changes in food intake. The data collectively suggest a critical role for melanocortin signaling in the control of energy balance.

Animals↗
PubMed2000

Intracerebroventricular insulin enhances memory in a passive-avoidance task.

Previous studies have indicated a possible enhancing effect of hyperinsulinemia on certain cognitive tasks in human subjects. Further, brain areas important in these tasks have high concentrations of insulin receptors, suggesting that insulin might modulate memory by activity at specific central sites. Extending this observation to the laboratory rat would provide a convenient model system for determining factors important for this possible cognitive effect. The present experiment determined whether intracerebroventricular administration of insulin improves memory formation in rats. Long-Evans rats were trained on a step-through passive-avoidance task, in which they were either shocked or not after entering a darkened compartment. After training, the animals received an intracerebroventricular injection of 4 mU insulin, heat-deactivated insulin or saline vehicle. After 24 h, the animals were tested for retention of the task. Rats receiving insulin after being shocked had an increased latency to enter the dark compartment, compared to those rats that had received saline or heat-deactivated insulin after shock. This difference is consistent with an enhanced memory for the negative consequences of entering.

Animals↗
PubMed2000

Adiposity signals and the control of energy homeostasis.

Recent technologic innovations have enabled probing the workings of individual cells and even molecules. As a result, our knowledge of the biological controls over eating and the regulation of body adiposity is increasing at a rapid pace. We review the evidence that food intake is controlled by separate but interacting groups of molecular signals. One group, termed satiety signals, are proportional to what is being consumed and help to determine meal size. Cholecystokinin is the best known of these, and its premeal administration causes a dose-dependent reduction of meal size. In and of itself, however, cholecystokinin (and other satiety signals) has little impact on body-fat stores. The second group, termed adiposity signals, circulate in proportion to body adiposity and enter the brain, where they interact with satiety signals in the brainstem and hypothalamus. Insulin and leptin are the best known of these adiposity signals, and the administration of either into the brain causes a dose-dependent reduction of both food intake and body weight. Within the brain, parallel but opposing pathways originating in the hypothalamic arcuate nuclei integrate adiposity signals with satiety signals. Those with a net anabolic effect increase food intake and reduce energy expenditure and are represented (among many such signals) by neuropeptide Y; those with a net catabolic effect decrease food intake and energy expenditure and are represented by brain melanocortins. This complex regulatory mechanism allows individuals to adapt their feeding schedule to idiosyncratic environmental constraints, eating whenever it is desirable or possible. Body-weight regulation occurs as adiposity signals alter the efficacy of meal-generated satiety signals.

Adipose Tissue↗
PubMed2000

Amylin and insulin interact to reduce food intake in rats.

We investigated the hypothesis that amylin and insulin, hormones co-secreted by pancreatic B-cells in response to a nutrient stimulus, interact to reduce food intake. A paradigm was employed that assessed food intake in adult male rats after bolus intravenous (i.v.) infusion at dark onset. In one experiment, rats received saline or amylin (0.1, 0.5 or 1.0 nmol). All amylin doses significantly suppressed 1 h intake, and although significant decreases in cumulative intake persisted for 2 h after 0.5 and 1.0 nmol, a significant increase of food intake actually occurred relative to saline during the interval from 1 to 2 h post-infusion. In another experiment, rats received saline, 0.25 nmol amylin, 10 mU insulin, or the combination of amylin plus insulin. Neither amylin nor insulin alone significantly changed cumulative food intake at any time point as compared to saline. However, the combination significantly reduced intake relative not only to saline but also to amylin and insulin alone after 1, 2, and 4 hours. These data are consistent with the hypothesis that endogenous amylin and insulin interact to reduce food intake and, ultimately, body weight.

Amyloid↗
PubMed2000

Food intake and the regulation of body weight.

This chapter reviews the recent literature on hormonal and neural signals critical to the regulation of individual meals and body fat. Rather than eating in response to acute energy deficits, animals eat when environmental conditions (social and learned factors, food availability, opportunity, etc.) are optimal. Hence, eating patterns are idiosyncratic. Energy homeostasis, the long-term matching of food intake to energy expenditure, is accomplished via controls over the size of meals. Individuals who have not eaten sufficient food to maintain their normal weight have lower levels of adiposity signals (leptin and insulin) in the blood and brain, and one consequence is that meal-generated signals (such as CCK) are less efficacious at reducing meal size. The converse is true if individuals are above their normal weight, when they tend to eat smaller meals. The final section reviews how these signals are received and integrated by the CNS, as well as the neural circuits and transmitters involved.

Animals↗
PubMed2000

Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade.

Overexpression of agouti-related peptide (AgRP), an endogenous melanocortin (MC) 3 and 4 receptor antagonist (MC3/4-R), causes obesity. Exogenous AgRP-(83---132) increases food intake, but its duration and mode of action are unknown. We report herein that doses as low as 10 pmol can have a potent effect on food intake of rats over a 24-h period after intracerebroventricular injection. Additionally, a single third ventricular dose as low as 100 pmol in rats produces a robust increase in food intake that persists for an entire week. AgRP-(83---132) completely blocks the anorectic effect of MTII (MC3/4-R agonist), given simultaneously, consistent with a competitive antagonist action. However, when given 24 h prior to MTII, AgRP-(83---132) is ineffective at reversing the anorectic effects of the agonist. These results support a critical role of MC tone in limiting food intake and indicate that the orexigenic effects of AgRP-(83---132) are initially mediated by competitive antagonism at MC receptors but are sustained by alternate mechanisms.

Agouti-Related Protein↗
PubMed2000

Amylin: a novel action in the brain to reduce body weight.

Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by pancreatic B cells in response to a nutrient stimulus (e.g., during meals). To test the hypothesis that amylin acts within the brain to reduce long-term food intake and body weight, we examined the effects of acute and chronic 3rd-ventricular (i3vt) infusion of low doses of amylin on food intake and body weight in rats. In one experiment, separate groups of ad lib-fed male Long Evans rats were given one i3vt infusion (3 microl over 30 s) of synthetic cerebrospinal fluid vehicle or 1 to 100 pmol amylin, and food intake and body weight were monitored for 7 days. Amylin potently and dose-dependently reduced 1-h food intake, with all doses producing significant reductions. The largest dose (100 pmol) significantly reduced 24-h intake by over 30%. The effect was persistent in that both 7-day cumulative food intake and body weight change were significantly decreased over the 7 days following a single injection of 100 pmol of amylin. Other groups of rats received continuous i3vt infusion (0.5 microl/h volume) of saline or 2.0 pmol/h amylin via osmotic minipumps over 10 days. Food intake over the 10-day infusion was significantly suppressed in amylin-treated rats as compared to that of controls. Consequently, by the 4th day of infusion, amylin rats weighed significantly less than baseline relative to saline controls, and this difference persisted throughout the remainder of the infusion period. At sacrifice (Day 10), the percent of body weight from retroperitoneal fat depots was significantly lower in the amylin-treated rats, indicative of a reduction of total body adiposity. In summary, the results support the hypothesis that amylin acts as a signal to the brain contributing to the maintenance of long-term energy balance.

Amyloid↗
PubMed1999

Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight.

Insulin and leptin are hypothesized to be 'adiposity signals' for the long-term regulation of body weight by the brain. Accordingly, a change in the plasma levels of leptin or insulin indicates a state of altered energy homeostasis and adiposity, and the brain responds by adjusting food intake to restore adipose tissue mass to a regulated level. The candidate site for the brain's detection of leptin adiposity signaling is the hypothalamic arcuate nucleus, where leptin inhibits expression neuropeptide Y and increases expression of the pro-opiomelanocortin (POMC) precursor of alphaMSH. Insulin also inhibits arcuate nucleus expression of neuropeptide Y but its effects on other hypothalamic signaling systems are not known. Leptin-responsive neurons in the arcuate nucleus are hypothesized to project to the paraventricular nucleus and lateral hypothalamic area where they are proposed to influence the expression of peptides that regulate food intake. Future development of this model will incorporate brain pathways for integration of leptin and insulin adiposity signaling to the hypothalamus with meal-related signals that act in the caudal brainstem. Recent research showing that leptin and insulin enhance the satiety action of peripheral CCK, thereby causing meals to be terminated earlier and reducing cumulative food intake, suggests that hypothalamic pathways that are sensitive to leptin and insulin adiposity signals have anatomical connections with caudal brainstem neurons that respond to meal-related signals and regulate meal size. The recent findings that insulin alters the expression and function of neural transporters for dopamine and norepinephrine indicate that adiposity signals may influence food intake by acting on non-peptide neurotransmitter systems.

Adipose Tissue↗
PubMed1999

Role of the CNS melanocortin system in the response to overfeeding.

The voluntary suppression of food intake that accompanies involuntary overfeeding is an effective regulatory response to positive energy balance. Because the pro-opiomelanocortin (POMC)-derived melanocortin system in the hypothalamus promotes anorexia and weight loss and is an important mediator of energy regulation, we hypothesized that it may contribute to the hypophagic response to overfeeding. Two groups of rats were overfed to 105 and 116% of control body weight via a gastric catheter. In the first group, in situ hybridization was used to measure POMC gene expression in the rostral arcuate (ARC). Overfeeding increased POMC mRNA in the ARC by 180% relative to levels in control rats. For rats in the second group, the overfeeding was stopped, and they were infused intracerebroventricularly with SHU9119 (SHU), a melanocortin (MC) antagonist at the MC3 and MC4 receptor, or vehicle. Although SHU (0.1 nmol) had no effect on food intake of control rats, intake of overfed rats increased by 265% relative to CSF-treated controls. This complete reversal of regulatory hypophagia not only maintained but actually increased the already elevated weight of overfed rats, whereas CSF-treated overfed rats lost weight. These results indicate that CNS MCs mediate hypophagic signaling in response to involuntary overfeeding and support the hypothesis that MCs are important in the central control of energy homeostasis.

Animals↗
PubMed1999

Nitrous oxide-induced hypothermia in the rat: acute and chronic tolerance.

Although inhalation of nitrous oxide (N2O) causes hypothermia in rats, there is a paucity of information as to whether tolerance develops to this effect. The purpose of this study was to determine whether tolerance to N2O hypothermia develops within a single administration as well as over repeated administrations. Temperature was measured telemetrically by implanting intraperitoneal thermal sensors/transmitters in male Long-Evans rats. Experimental rats received an initial 2-h exposure to 60% N2O and became hypothermic relative to controls breathing placebo gas. Only a few rats demonstrated evidence of acute tolerance over the 120 min. Over the next 10 days, the experimental rats received five additional 30-min exposures to 60% N2O and five 30-min exposures to placebo while the control rats received only placebo gas exposures. Chronic tolerance developed to N2O hypothermia over these repeated administrations. A test for Pavlovian drug conditioning found no evidence that conditioned temperature effects contributed to chronic tolerance development. In a second experiment, naive rats were given a 380-min exposure to 60% N2O and a 380-min exposure to placebo gas in a counterbalanced order. Acute tolerance did develop to N2O hypothermia, with the recovery of temperature beginning after a mean of 141 min of gas administration. Hence, both acute and chronic tolerance develop to N2O's hypothermic effects in rats.

Administration, Inhalation↗
PubMed1999

Neuroendocrine regulation of food intake.

Maintenance of appropriate stores of metabolic fuels depends on carefully matching caloric intake to caloric expenditure. Achieving such 'energy balance' is a product of complex interactions of peripheral hormones with effector systems in the central nervous system (CNS) that regulate food intake and energy expenditure. Leptin is a hormone that is made in the adipocytes, circulates in the blood and interacts with receptors in the CNS. These receptors can be found in two different types of systems. One effector system is termed 'anabolic' and is activated by low levels of leptin during negative energy balance. This system (exemplified by the hypothalamic neuropeptide Y system) increases food intake and decreases energy expenditure to facilitate the regaining of lost energy stores. The other effector system is termed 'catabolic' and is activated by high levels of leptin during positive energy balance. This system (exemplified by the hypothalamic melanocortin and corticotrophin-releasing hormone systems) decreases food intake and increases energy expenditure to facilitate the loss of excess energy stores. Further understanding of these systems is necessary to develop adequate treatments for disorders of energy balance, such as obesity and wasting.

Animals↗
PubMed1999

Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat.

To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 micrograms) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin's anorexigenic action.

Animals↗
PubMed1999

Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mRNA in the arcuate nucleus.

Reduced leptin (Ob protein) signaling is proposed to be a stimulus for the activation of neuropeptide Y (NPY) gene activity and increased expression of mRNA for the long form of the leptin receptor (Ob-Rb) in the hypothalamic arcuate nucleus. To determine if Ob-Rb protein is expressed in arcuate nucleus NPY neurons, we developed an affinity-purified polyclonal antibody against amino acids 956-1102 of human Ob-Rb. This antibody specifically recognizes the cytoplasmic tail of Ob-Rb and does not react with shorter leptin-receptor variants. Western immunoblots of Ob-Rb-transfected COS cells showed a single 150-kD band, and immunofluorescence revealed intense perinuclear staining in the cytoplasm. A 150-kD band was also present in Western immunoblots of hypothalamus. Immunocytochemical staining of brain slices revealed immunoreactive Ob-Rb protein concentrated in many neuronal cell bodies in the same regions of the forebrain that also express Ob-Rb mRNA. In the hypothalamus, Ob-Rb-positive cell bodies were abundant in the arcuate nucleus and ventromedial nucleus, with lesser numbers in the dorsomedial nucleus and paraventricular nucleus. Immunostaining was also detected in cell bodies of pyramidal cell neurons of the pyriform cortex and cerebral cortex, in neurons of the thalamus, and on the surface of ependymal cells lining the third ventricle. The choroid plexus, which expresses the short Ob-Ra form, was negative. Combined immunocytochemistry for Ob-Rb protein and fluorescence in situ hybridization for NPY mRNA identified arcuate nucleus neurons containing both NPY mRNA and Ob-Rb protein. The present finding of Ob-Rb protein in neurons that express NPY mRNA supports the hypothesis that arcuate nucleus NPY neurons are direct targets of leptin and play an important role in regulation of food intake and body weight.

Alternative Splicing↗
PubMed1999

Cerebrospinal fluid and plasma leptin measurements: covariability with dopamine and cortisol in fasting humans.

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.

Adult↗