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R J Seeley

Publications and source records attributed to R J Seeley.

At least 19 recordsLinked to original sources
PubMed2004

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.

Animals↗
PubMed2003

Assessment of the aversive consequences of acute and chronic administration of the melanocortin agonist, MTII.

BACKGROUND: The synthetic melanocortin (MC) agonist, melanotan-II (MTII), reduces food intake and body weight for hours to days after administration. One early report on the effect of MTII suggested that part of its anorexic action may be mediated by aversive consequences. In that experiment, MTII was found to support a mild conditioned taste aversion (CTA). OBJECTIVE: The present experiments replicate and extend those findings in two additional CTA paradigms to further characterize the aversive effects of MTII in rats. METHODS: Experiment 1 simultaneously assessed the ability of MTII to support CTA and reduce food intake, using a small oral infusion of a novel taste as the conditioned stimulus. Experiment 2 assessed the aversive consequences of chronic MTII administration. To accomplish this, we paired implantation of lithium chloride (LiCl)-, MTII- or saline-containing osmotic minipumps with a constantly available novel flavor. After 7 days, rats received a choice test between the minipump-paired flavor and a previously available neutral flavor. RESULTS: Rats with saline minipumps exhibited no preference for either flavor. By contrast, rats in both the LiCl and MTII minipump groups significantly preferred the neutral flavor, indicating the development of a CTA. Additionally, CTA produced by administration of MTII was found to be more resistant to extinction than that produced by LiCl. CONCLUSIONS: The reduction in food intake caused by MTII is accompanied by aversive consequences regardless of route of administration. These results present difficulties for the development of MCs-based therapies for obesity.

Animals↗
PubMed2002

Understanding the physiology of obesity: review of recent developments in obesity research.

Knowledge of the genetic and regulatory factors that influence energy homeostasis is advancing rapidly. There is increased understanding of the molecular signals that reach the brain with information regarding the current state of energy balance, how those signals are detected by the brain, and key neuronal systems important in translating the information into efferent responses. The identification of molecules that control food intake has generated new targets for drug development in the treatment of obesity. In view of the complexities of the energy control system, therapeutic strategies that target only one site are likely to be less effective than those targeting two or more sites.

Adipose Tissue↗
PubMed2002

Combined blockade of both micro - and kappa-opioid receptors prevents the acute orexigenic action of Agouti-related protein.

Agouti-related protein (AgRP) is an endogenous antagonist at the melanocortin 3 and 4 receptor in the hypothalamus. Central administration of AgRP produces a robust increase in food intake, and this effect can be blocked by administration of nonspecific opioid receptor antagonist. Such results implicate opioid receptors as critical to mediating the effects of AgRP. To determine which opioid receptor subtype is critical, we first determined the highest i3vt (administered into the third ventricle) dose of two specific opioid antagonists, nor-Binaltorphine or beta-funaltrexamine, that did not influence food intake on their own. Then, rats were pretreated with either of these two antagonists before i3vt AgRP and access to a high-fat diet. For neither the kappa- nor the micro -specific antagonist was there any effect to block the effects of AgRP on food intake. However, administration of both the kappa- and micro -receptor antagonists does significantly reduce the effect of AgRP. The current results implicate opioid receptors as critical downstream mediators of the potent effects of AgRP to increase food intake but indicate that either micro - or kappa-receptor activation is sufficient for AgRP's effect.

Agouti-Related Protein↗
PubMed2001

Activity of body energy regulatory pathways in inflammation-induced anorexia.

Previous research has shown that reductions in body weight prior to induction of acute inflammation can attenuate inflammation-induced anorexia in male rats. In the current study, potential mechanisms responsible for this observation were examined. Specifically, the effect of a 12% prior reduction in body weight on serum leptin, insulin, and corticosterone; levels of interleukin-1 (IL-1), interleukin-6 (IL-6) in the serum, liver, and spleen; neuropeptide Y (NPY) and POMC mRNA levels in the arcuate nucleus (ARC) of the hypothalamus were examined 8 h after induction of acute inflammation. Rats with prior weight reduction had significantly lower serum leptin levels and gene expression of POMC in the ARC than normal-weight rats. In contrast, prior weight reduction altered neither NPY mRNA in the ARC, nor IL-1alpha, IL-1beta, and IL-6 levels in the serum, liver, and spleen. These results suggest that the attenuation of inflammation-induced anorexia by prior weight reduction is not due to altered cytokine activity, but rather to changes in energy regulatory systems that moderate the anorexic actions of IL-1beta and IL-6. One potential change may be reduced activity of the CNS melanocortin system induced by decreased circulating leptin.

Adipose Tissue↗
PubMed2001

Insulin as an adiposity signal.

Insulin is now well established as an adiposity signal that acts in the brain to influence energy homeostasis. It is secreted in direct proportion to adiposity; it enters the brain from the blood, and it interacts with neurons in the ventral hypothalamus. Experimental manipulation of brain insulin causes predictable changes of food intake and body weight. Because insulin shares many properties with other adiposity signals, especially leptin, in this regard, it is important to recognize the similarities and differences in the signal each conveys to the brain in order to design effective therapeutic approaches to treat pathologies of eating and body weight.

Adipose Tissue↗
PubMed2001

Opioid receptor involvement in the effect of AgRP- (83-132) on food intake and food selection.

Agouti-related peptide (AgRP) is a receptor antagonist of central nervous system (CNS) melanocortin receptors and appears to have an important role in the control of food intake since exogenous CNS administration in rats and overexpression in mice result in profound hyperphagia and weight gain. Given that AgRP is heavily colocalized with neuropeptide Y (NPY) and that orexigenic effects of NPY depend on activity at opioid receptors, we hypothesized that AgRP's food-intake effects are also mediated by opioid receptors. Subthreshold doses of the opioid receptor antagonist naloxone blocked AgRP-induced intake when given simultaneously but not 24 h after AgRP injection. Opioids not only influence food intake but food selection as well. Hence, we tested AgRP's effect to alter food choice between matched diets with differing dietary fat content. AgRP selectively enhanced intake of the high-fat but not the low-fat diet. Additionally, AgRP selectively increased chow intake in rats given ad libitum access to a 20% sucrose solution and standard rat chow. The current results indicate that AgRP influences not only caloric intake but food selection as well and that the early effects of AgRP depend critically on an interaction with opioid receptors.

Agouti-Related Protein↗
PubMed2001

Intestinal satiety protein apolipoprotein AIV is synthesized and regulated in rat hypothalamus.

Apolipoprotein AIV (apo AIV) is a satiety protein secreted by the small intestine. We demonstrate for the first time that apo AIV protein and apo AIV mRNA are present in rat hypothalamus, a site intimately involved in the integration of signals for regulation of food intake and energy metabolism. We further characterized the regulation of hypothalamic apo AIV mRNA levels. Food-deprived animals showed a pronounced decrease in gene expression of apo AIV in the hypothalamus, with a concomitant decrease in the jejunum. Refeeding fasted rats with standard laboratory chow for 4 h evokes a significant increase of apo AIV mRNA in jejunum but not in hypothalamus. However, lipid refeeding to the fasted animals restored apo AIV mRNA levels both in hypothalamus and jejunum. Intracerebroventricular administration of apo AIV antiserum not only stimulated feeding, but also decreased apo AIV mRNA level in the hypothalamus. These data further confirm the central role of apo AIV in the regulation of food intake.

Animals↗
PubMed2001

Effect of leptin on intestinal apolipoprotein AIV in response to lipid feeding.

We determined apolipoprotein AIV (apo AIV) content in intestinal epithelial cells using immunohistochemistry when leptin was administered intravenously. Most of the apo AIV immunoreactivity in the untreated intestine was located in the villous cells as opposed to the crypt cells. Regional distribution of apo AIV immunostaining revealed low apo AIV content in the duodenum and high content in the jejunum that gradually decreases caudally toward the ileum. Intraduodenal infusion of lipid (4 h) significantly increased apo AIV immunoreactivity in the jejunum and ileum. Simultaneous intravenous leptin infusion plus duodenal lipid infusion markedly suppressed apo AIV immunoreactivity. Duodenal lipid infusion increased plasma apo AIV significantly (measured by ELISA), whereas simultaneous leptin infusion attenuated the increase. These findings suggest that leptin may regulate circulating apo AIV by suppressing apo AIV synthesis in the small intestine.

Animals↗
PubMed2001

Inhibition of central amylin signaling increases food intake and body adiposity in rats.

Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by pancreatic beta cells in response to feeding. We recently reported that amylin potently reduces food intake, body weight, and adiposity when delivered into the 3rd cerebral ventricle (i3vt) of rats. We have now infused i3vt a specific antagonist (AC187) to ascertain the physiological relevance of central amylin in the control of energy balance. After establishing the ability of i3vt AC187 to block the anorexic effect of i3vt amylin, we performed an experiment to examine the impact of acute inhibition of central amylin signaling on feeding. Separate groups (n = 7/group) of ad lib-fed male Long Evans rats were given one bolus i3vt infusion of synthetic cerebrospinal fluid vehicle (CSF) or AC187 (250 or 1000 pmol). Acute infusion of AC187 tended to increase 1-h food intake and significantly elevated 4-h intake. Both the 250 and 1000 pmol doses produced significant increases as compared to CSF. In another experiment designed to tonically inhibit central amylin signaling over an extended period, two other groups of rats (n = 6/group) received continuous i3vt infusion of CSF or 100 pmol/h AC187 over 14 days via implantable osmotic pumps. Rats receiving AC187 ate significantly more food over the 14-day infusion period relative to controls (CSF = 322 +/- 6 g, AC187 = 360 +/- 12 g). Although body weight was not significantly affected, body fat was increased by about 30% in the AC187 rats, with no difference in lean tissue between the groups. Additionally, although fasting plasma glucose did not differ between the CSF and AC187 groups after 14 days of infusion, plasma insulin was significantly elevated in the AC187 rats. In summary, the present results document significant increases of food intake and body adiposity resulting from inhibition of central amylin signaling. They are consistent with our hypothesis that CNS actions of endogenous amylin contribute to the long-term regulation of energy balance.

Adipose Tissue↗
PubMed2001

Immediate and prolonged patterns of Agouti-related peptide-(83--132)-induced c-Fos activation in hypothalamic and extrahypothalamic sites.

Several lines of evidence substantiate the important role of the central nervous system melanocortin 3- and 4-receptor (MC3/4-R) system in the control of food intake and energy balance. Agouti-related peptide (AgRP), an endogenous antagonist of these receptors, produces a robust and unique pattern of increased food intake that lasts up to 7 days after a single injection. Little is known about brain regions that may mediate this powerful effect of AgRP on food intake. To this end we compared c-Fos-like immunoreactivity (c-FLI) in several brain sites of rats injected intracerebroventricularly with 1 nmol AgRP-(83--132) 2 and 24 h before death and compared c-FLI patterns to those induced by another potent orexigenic peptide, neuropeptide Y (NPY). Although both NPY and AgRP induced c-FLI in hypothalamic areas, AgRP also produced increased c-FLI in the accumbens shell and lateral septum. Although NPY elicited no changes in c-FLI 24 h after administration, AgRP induced c-FLI in the accumbens shell, nucleus of the solitary tract, central amygdala, and lateral hypothalamus. These results indicate that an NPY-like hypothalamic circuit mediates the short-term effects of AgRP, but that the unique sustained effect of AgRP on food intake involves a complex circuit of key extrahypothalamic reward and feeding regulatory nuclei.

Agouti-Related Protein↗
PubMed2000

Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss.

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm. Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.

Agouti-Related Protein↗
PubMed2000

A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences.

Studies using nonselective agonists and antagonists of melanocortin-3 receptor (MC3R) and MC4R point to the importance of the CNS melanocortin system in the control of food intake. We describe here a novel compound that is highly selective as an agonist at the MC4 receptor but has minimal activity at the MC3 receptor. When administered centrally to rats, this selective agonist increased Fos-like immunoreactivity in the paraventricular nucleus, central nucleus of the amygdala, nucleus of the solitary tract, and area postrema, a pattern of neuronal activation that is similar to that induced by a nonselective MC3/4R agonist. Additionally, it suppresses food intake when administered centrally to rats or peripherally to db/db mice that lack functional leptin receptors via a mechanism that is not accompanied by illness or other nonspecific effects. Conversely, a related compound that is a selective MC4R antagonist potently increased food intake when administered centrally in rats. These results support the hypothesis that the brain MC4R is intimately involved in the control of food intake and body weight and provide evidence that selective activation of MC4R causes anorexia that is not secondary to aversive effects.

Animals↗
PubMed2000

Central nervous system control of food intake.

New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

Biogenic Monoamines↗
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↗