0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Implications of Basic Neuroscience Research |

Implications of Amylin Receptor Agonism:  Integrated Neurohormonal Mechanisms and Therapeutic Applications FREE

Jonathan D. Roth, PhD; Holly Maier, PhD; Steve Chen, MD; Barbara L. Roland, PhD
[+] Author Affiliations

Author Affiliations:Amylin Pharmaceuticals, Inc, San Diego, California.


Section Editor: Hassan M. Fathallah-shaykh, MD, PhD

More Author Information
Arch Neurol. 2009;66(3):306-310. doi:10.1001/archneurol.2008.581.
Text Size: A A A
Published online

Amylin receptor agonism is emerging as part of an integrated neurohormonal therapeutic approach for managing diabetes mellitus (DM) and body weight. Pramlintide acetate, an analogue of the pancreatic hormone amylin, has been studied in the United States as an antihyperglycemic agent in patients with type 1 or type 2 DM treated with mealtime insulin.1Further clinical testing of pramlintide in subjects with obesity demonstrated that pramlintide monotherapy induced significant, sustained, and dose-dependent weight loss.2Recent clinical observations point to its compatibility as a combination therapy with the hormone leptin, eliciting double-digit weight loss in patients with overweight and obesity.3Herein, we link amylin activation of central neural circuits to these therapeutic effects, and we speculate on other potential therapeutic applications of amylin receptor agonism.

Amylin is a 37–amino acid peptide hormone cosecreted with insulin from pancreatic β cells. In rodents and humans, plasma amylin concentrations rapidly rise several-fold in response to meals, with a diurnal profile that is almost superimposable on that of insulin.1The physiologic effects of amylin receptor agonism include (1) decreased food intake,1,4(2) slowing of the rate of gastric emptying,1,5and (3) reduction of postprandial glucagon release in a glucose-dependent manner.1,6Through these mechanisms, amylin receptor agonism reduces the rate of glucose entry into the bloodstream after meals to better match the ability of insulin to dispose of blood glucose.

On secretion into the circulation, amylin binds with high affinity to receptors in the central nervous system (Figure). Within the brain, amylin-specific receptors, which are composed of the calcitonin receptor partnered with individual receptor-modifying proteins, are located in the nucleus accumbens, the dorsal raphe, and the hindbrain area postrema.7There is evidence of specific binding of amylin to receptors located in the nucleus accumbens and dorsal raphe,7but, because these areas reside within the blood-brain barrier, it is unlikely that their cognate ligand is circulating amylin. The role of these binding sites remains to be elucidated.

Place holder to copy figure label and caption
Figure.

Amylin neural circuit key sites and activation pathways in the rat. The area postrema is located outside the blood-brain barrier and contains neurons that are directly activated by peripheral amylin, propagating signals to the adjacent nucleus of the solitary tract, the lateral parabrachial nucleus, and the central nucleus of the amygdala. Lesions in the area postrema abrogate the anorexigenic effects of amylin, as well as amylin-induced c-fos expression in the nucleus of the solitary tract, the lateral parabrachial nucleus, and the central nucleus of the amygdala. While binding is evident in other regions residing within the blood-brain barrier using ex vivo autoradiography, the cognate ligand for these binding sites remains to be elucidated. Effects of amylin-dependent neuronal activation include reduced hunger signals, modulation of fasting-induced lateral hypothalamic activation, augmentation of leptin signaling in the ventromedial nucleus of the hypothalamus, and potential antianxiolytic properties.

Graphic Jump Location
Area Postrema

The area postrema (Figure), which lacks a blood-brain barrier, has a pivotal role in mediating the physiologic effects of amylin by receiving and integrating peripheral meal-related signals.8Approximately 90% of neurons in the area postrema that express amylin-specific receptors also express glucose-sensing receptors.9In a rat model, lesions in the area postrema reduced the anorexigenic and gastric emptying effects of peripherally administered amylin, identifying the area postrema as an essential location for amylin activity.10,11Similarly, blockade of endogenous amylin in the area postrema via central administration of the selective amylin antagonist AC187 increased food intake and reversed the anorexigenic effects of peripherally administered amylin.12The amylin antagonist AC187 also raised glucagon concentrations, accelerated gastric emptying of liquids, and increased glycemia after an oral nutrient challenge, consistent with a central role of amylin in regulating nutrient intake and use.13

Nucleus of the Solitary Tract, Lateral Parabrachial Nucleus, and Central Amygdala

Whereas the hindbrain area postrema clearly contains the “first-order” set of neurons that transduce the effects of peripheral amylin, amylin affects other areas of the brain via well-established neural pathways. Major reciprocal projections exist between the area postrema, the adjacent nucleus of the solitary tract, and the lateral parabrachial nucleus (Figure).8In turn, the lateral parabrachial nucleus projects to the central nucleus of the amygdala.14These nuclei seem to be sequentially stimulated (as measured by c-fos, a marker of neuronal activation) in response to amylin receptor stimulation in the area postrema, collectively mediating the anorexigenic effects of amylin. Lesions of the area postrema abolish neuronal activation in the lateral parabrachial nucleus and the central nucleus of the amygdala,12,15whereas lesions of the lateral parabrachial nucleus abrogate signaling in the central nucleus of the amygdala following amylin administration.16

Hypothalamus

The importance of amylin in modulating hypothalamic responses to nutritional status and other weight regulatory signals has been established in several nonclinical studies in lean or diet-induced obese rodents. In short-term investigations in lean animals, peripheral amylin injection reversed fasting-induced c-fos expression in the lateral hypothalamic area,12mirroring the effects of refeeding, and downregulated the expression of lateral hypothalamic orexigenic genes.17These effects are likely indirect because amylin binding has not been reported in this nucleus.18The anorexigenic effects of amylin may also include cross-talk with hypothalamic histaminergic signaling pathways because histaminergic receptor blockade within the ventromedial hypothalamus blunted the anorexigenic effects of amylin.19Finally, the short-term satiating effect of peripheral amylin was enhanced by central administration of the adiposity signals leptin or insulin, which act in the hypothalamus to reduce feeding.20In diet-induced obese leptin-resistant rats, the effects of peripheral amylin treatment were consistent with enhanced central responsiveness to leptin. Amylin-mediated weight loss (but not caloric restriction) was associated with increased pro-opiomelanocortin gene expression (a downstream target of leptin and the precursor of the anorectic α-msh) within the arcuate nucleus.21In addition, whereas vehicle-treated diet-induced obese rats have diminished hypothalamic leptin signaling, pretreatment with amylin (but not caloric restriction) for 1 week restored leptin-induced neuronal activation (eg, pSTAT-3 [phosphorylated STAT3] signaling) within the ventromedial hypothalamus.3

Other Regions of the Brain

It is possible that pharmacologic levels of amylin engage additional neural circuits. Rich amylin binding has been demonstrated in the nucleus accumbens, a key brain region mediating food reward, suggesting that amylin signaling may influence hedonic responses to food.22Consistent with this hypothesis, food choice experiments showed that intake of highly palatable (high-fat or high-sucrose) foods was selectively decreased during short- and long-term amylin treatments.23However, it is unlikely that endogenous circulating levels of amylin cross the blood-brain barrier to directly activate this nucleus. The mechanism of the role of amylin in food reward remains to be explored.

In summary, these preclinical findings demonstrate a role for amylin receptor agonism in regulating blood glucose concentrations and in integrating feeding-, gut-, and taste-related signaling. Amylin transmits the integrated information to upstream nuclei involved in energy balance and possibly mediates food reward.

The ability of amylin to stimulate key neural circuits involved in blood glucose regulation and food intake led to the investigation of amylin analogues as treatments for metabolic diseases. Herein, we highlight how amylin-dependent activation of neural circuits can be leveraged in the treatment of DM and potentially in obesity and neuropsychiatric diseases.

Diabetes Mellitus

Diabetes mellitus is characterized by hyperglycemia resulting from defects in the secretion or action of multiple hormones, including insulin, amylin, glucagon, and glucagonlike peptide 1. Dysfunction of pancreatic β cells is a core defect in DM that results in reduced (type 2 DM) or absent (type 1 DM) secretion of insulin and amylin in response to food intake. Insulin therapy is a common treatment for patients with DM. However, many patients who use insulin are unable to maintain adequate glycemic control perhaps in part because of the continued dysregulation of other hormones such as amylin.

Pramlintide, an analogue of human amylin, was developed to overcome several physicochemical properties that make human amylin unsuitable for pharmacologic delivery. By mimicking the aforementioned neurohormonal actions of amylin, pramlintide complements the actions of insulin by regulating the presence of glucose in the circulation via slowed gastric emptying, reduced food intake, and decreased postprandial glucagon secretion.1In clinical investigations of patients with type 1 or type 2 DM, pramlintide reduced glycated hemoglobin and postprandial glucose excursions with a concomitant reduction in insulin dosage, improving overall glycemic control compared with insulin treatment alone.1In addition, pramlintide treatment generally led to weight loss, while insulin treatment tended to promote weight gain.1The most frequent treatment-emergent adverse events with pramlintide use were mild to moderate insulin-induced hypoglycemia and nausea, which decreased over time. Collectively, findings from these studies suggest that pramlintide in combination with insulin provides a physiologic approach to the treatment of DM by mimicking the effects of amylin.

Obesity

Results of preclinical investigations suggest that amylin may be useful for treating obesity.24Amylin administered peripherally to rodents decreased meal size and increased the ratio of postmeal interval to meal size (a measure of satiety in humans) without any indication of malaise (kaolin intake, locomotor activity, or taste aversion).23,24Reductions in food intake and body weight have been maintained for up to 11 weeks of treatment with continuous peripheral amylin administration in rat models of diet-induced obesity.23The weight-reducing effects of amylin are dose dependent, are not associated with compensatory decreases in energy expenditure, and are attributed to the loss of fat mass with relative preservation of lean mass.3,21,23,25Whereas reduced food intake is the predominant mechanism of overall weight loss, pair-feeding investigations demonstrate that amylin-treated rats lose more fat than would be predicted due to caloric restriction alone.21

These preclinical findings with amylin, along with the observation that pramlintide therapy reduced body weight in patients with insulin-treated DM, pointed to its potential clinical usefulness as an antiobesity agent. In subjects with obesity, pramlintide elicited significant weight loss in the absence of lifestyle intervention.26,27When used in conjunction with lifestyle intervention, pramlintide use led to greater initial weight loss compared with placebo (≤5.7% vs 2.6% at 4 months) and longer maintenance of weight loss (≤7.9% vs 1.1% at 12 months).2The most common adverse event in these studies was mild to moderate nausea, which decreased over time.

Monotherapies that target a single aspect of the multihormonal dysregulation associated with obesity may be limited in efficacy by compensatory mechanisms that favor weight maintenance and regain. For example, weight loss and energy restriction (as encountered during dieting or with drug treatment) trigger a cascade of events to defend body weight, including a fall in leptin level (due to fat loss), decreased sympathetic nervous system activity, increased muscle work efficiency, reduced energy expenditure and metabolic rate, increased hunger, and decreased satiety and fullness.28There is a growing consensus that overcoming these compensatory mechanisms will require combination therapies that target multiple mechanisms regulating body weight. Our translational obesity research program has recently explored the following 2 combinatorial strategies: (1) amylin-leptin agonism to harness short-term satiety and long-term adiposity signaling and (2) amylin receptor agonism combined with approved small-molecule anorectics that act via classic neurotransmitter systems.

Preclinical studies demonstrated synergistic weight and fat loss when amylin was coadministered with leptin in rats with diet-induced obesity3,29and additive weight loss when amylin was coadministered with the small-molecule anorectics sibutramine hydrochloride or phentermine hydrochloride.30In a randomized double-blind clinical proof-of-concept study3in subjects with overweight and obesity, coadministration of metreleptin and pramlintide acetate for 20 weeks (after a 4-week lead-in treatment period with pramlintide alone) elicited significantly more weight loss (approximately 13%) than either treatment alone. In a randomized 24-week single-blind study31(only the subjects were blinded to study medication), the combination of pramlintide with sibutramine or phentermine significantly increased weight loss (approximately 11 kg) compared with pramlintide monotherapy (approximately 4 kg). The safety profiles in both of these studies were consistent with those of the individual treatments, suggesting that targeting multiple pathways through the combination of an amylin agonist and centrally acting anorectic agents may lead to enhanced weight loss without the emergence of unexpected adverse events. Together, the findings of these studies suggest that a combinatorial approach that includes pramlintide may successfully override the central nervous system mechanisms for defending body weight.

Neuropsychiatric Disease

Amylin activation of central neural circuits may also have therapeutic potential in the treatment of neuropsychiatric diseases. It is increasingly clear that the neural circuitry modulating energy homeostasis interacts and even overlaps with circuits involved in cognition, reward, and stress.32Hence, the peptides and proteins propagating these signals may have beneficial emotional or behavioral effects, as well as effects on metabolic (or energy-related) processes.

In preclinical studies, amylin receptor agonism has recently been associated with anxiolytic and antidepressant properties. Long-term stress triggers a dietary imbalance that increases palatable feeding and visceral obesity through resetting of the hypothalamic-pituitary-adrenal axis.33,34When standard chow and sucrose were made freely available to rats, amylin administration not only decreased preference for sucrose but also prevented stress-induced sucrose consumption following restraint stress.35In models of depression and anxiety, amylin decreased immobility in the forced swim test, reduced marble burying, increased the number of crossings in the 4-plate test, and attenuated the hyperthermic response to restraint stress, which was blocked following lesioning of the area postrema.36,37Furthermore, stress-induced c-fos activation in central circuits was reduced with amylin treatment.36Although these intriguing preclinical observations require clinical validation, they suggest that the integrated mechanisms of amylin may improve metabolic and behavioral processes.

The direct and indirect effects of amylin receptor agonism are summarized in the Table. In addition to its known therapeutic effects on glycemic control in patients with type 1 or type 2 DM using insulin, amylin receptor agonism is emerging as a novel potential therapy for obesity as monotherapy or in combination therapy. It is increasingly clear that activation of the amylin neural circuit may have usefulness beyond the treatment of metabolic diseases. Nonclinical evidence suggests therapeutic potential of amylin in neuropsychiatric diseases. Further research on amylin receptor agonism in several other therapeutic areas is clearly warranted. Recent efforts to develop additional amylin analogues have indicated that it is possible to enhance specific amylin actions. For example, the amylin analogue AC2307 was recently shown to be more potent and to elicit greater weight loss relative to native amylin in nonclinical investigations.38To what extent specific amylin actions can be individually optimized to treat various disease states remains to be determined.

Table Graphic Jump LocationTable. Direct and Indirect Effects of Amylin Receptor Agonism

Correspondence:Jonathan D. Roth, PhD, Amylin Pharmaceuticals, Inc, 9360 Towne Centre Dr, San Diego, CA 92121 (jonathan.roth@amylin.com).

Accepted for Publication:November 21, 2008.

Author Contributions:Study concept and design: Roth and Roland. Acquisition of data: Roland. Analysis and interpretation of data: Maier, Chen, and Roland. Drafting of the manuscript: Roth, Maier, and Roland. Critical revision of the manuscript for important intellectual content: Roth, Chen, and Roland. Administrative, technical, and material support: Maier. Study supervision: Roth, Chen, and Roland.

Financial Disclosure:All authors are employed by and own stock in Amylin Pharmaceuticals, Inc.

Pullman  JDarsow  TFrias  JP Pramlintide in the management of insulin-using patients with type 2 and type 1 diabetes. Vasc Health Risk Manag 2006;2 (3) 203- 212
PubMed Link to Article
Smith  SRAronne  LJBurns  CMKesty  NCHalseth  AEWeyer  C Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care 2008;31 (9) 1816- 1823
PubMed Link to Article
Roth  JDRoland  BLCole  RL  et al.  Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci U S A 2008;105 (20) 7257- 7262
PubMed Link to Article
Lutz  TADel Prete  EScharrer  E Reduction of food intake in rats by intraperitoneal injection of low doses of amylin. Physiol Behav 1994;55 (5) 891- 895
PubMed Link to Article
Young  AAGedulin  BVine  WPercy  ARink  TJ Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin. Diabetologia 1995;38 (6) 642- 648
PubMed Link to Article
Silvestre  RARodríguez-Gallardo  JJodka  C  et al.  Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas. Am J Physiol Endocrinol Metab 2001;280 (3) E443- E449Accessed December 6, 2008
PubMed
Young  A Receptor pharmacology. Adv Pharmacol 2005;5247- 65
PubMed
Price  CJHoyda  TDFerguson  AV The area postrema: a brain monitor and integrator of systemic autonomic state. Neuroscientist 2008;14 (2) 182- 194
PubMed Link to Article
Riediger  TSchmid  HALutz  TASimon  E Amylin and glucose co-activate area postrema neurons of the rat. Neurosci Lett 2002;328 (2) 121- 124
PubMed Link to Article
Lutz  TASenn  MAlthaus  JDel Prete  EEhrensperger  FScharrer  E Lesion of the area postrema nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene–related peptide (CGRP) in rats. Peptides 1998;19 (2) 309- 317
PubMed Link to Article
Edwards  GLGedulin  BRJodka  CDilts  RPMiller  CCYoung  A Area postrema (AP)–lesions block the regulation of gastric emptying by amylin [abstract]. Neurogastroenterol Motil 1998;10 (4) 26
Riediger  TZuend  DBecskei  CLutz  TA The anorectic hormone amylin contributes to feeding-related changes of neuronal activity in key structures of the gut-brain axis. Am J Physiol Regul Integr Comp Physiol 2004;286 (1) R114- R122
PubMed Link to Article
Gedulin  BRJodka  CMHerrmann  KYoung  AA Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187. Regul Pept 2006;137 (3) 121- 127
PubMed Link to Article
Block  CHHoffman  GKapp  BS Peptide-containing pathways from the parabrachial complex to the central nucleus of the amygdala. Peptides 1989;10 (2) 465- 471
PubMed Link to Article
Rowland  NERichmond  RM Area postrema and the anorectic actions of dexfenfluramine and amylin. Brain Res 1999;820 (1-2) 86- 91
PubMed Link to Article
Becskei  CGrabler  VEdwards  GLRiediger  TLutz  TA Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK. Brain Res 2007;116276- 84
PubMed Link to Article
Barth  SWRiediger  TLutz  TARechkemmer  G Differential effects of amylin and salmon calcitonin on neuropeptide gene expression in the lateral hypothalamic area and the arcuate nucleus of the rat. Neurosci Lett 2003;341 (2) 131- 134
PubMed Link to Article
Sexton  PMPaxinos  GKenney  MAWookey  PJBeaumont  K In vitro autoradiographic localization of amylin binding sites in rat brain. Neuroscience 1994;62 (2) 553- 567
PubMed Link to Article
Mollet  AMeier  SRiediger  TLutz  TA Histamine H1 receptors in the ventromedial hypothalamus mediate the anorectic action of the pancreatic hormone amylin. Peptides 2003;24 (1) 155- 158
PubMed Link to Article
Osto  MWielinga  PYAlder  BWalser  NLutz  TA Modulation of the satiating effect of amylin by central ghrelin, leptin and insulin. Physiol Behav 2007;91 (5) 566- 572
PubMed Link to Article
Roth  JDHughes  HKendall  EBaron  ADAnderson  CM Antiobesity effects of the β-cell hormone amylin in diet-induced obese rats: effects on food intake, body weight, composition, energy expenditure, and gene expression. Endocrinology 2006;147 (12) 5855- 5864
PubMed Link to Article
Kelley  AEBaldo  BAPratt  WEWill  MJ Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. Physiol Behav 2005;86 (5) 773- 795
PubMed Link to Article
Mack  CWilson  JAthanacio  J  et al.  Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference and body weight. Am J Physiol Regul Integr Comp Physiol 2007;293 (5) R1855- R1863
PubMed Link to Article
Young  A Inhibition of food intake. Adv Pharmacol 2005;5279- 98
PubMed
Roth  JDHughes  HCoffey  TMaier  HTrevaskis  JLAnderson  CM Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat–fed female rats. Am J Physiol Endocrinol Metab 2007;293 (4) E1112- E1117
PubMed Link to Article
Aronne  LFujioka  KAroda  V  et al.  Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab 2007;92 (8) 2977- 2983
PubMed Link to Article
Smith  SRBlundell  JEBurns  C  et al.  Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study. Am J Physiol Endocrinol Metab 2007;293 (2) E620- E627Accessed December 6, 2008
PubMed Link to Article
Chen  HCRoth  JDSchroeder  BEWeyer  C Role of islet-, gut-, and adipocyte-derived hormones in the central control of food intake and body weight: implications for an integrated neurohormonal approach to obesity pharmacotherapy. Curr Diabetes Rev 2008;4 (2) 79- 91
PubMed Link to Article
Trevaskis  JLCoffey  TCole  R  et al.  Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms. Endocrinology 2008;149 (11) 5679- 5687
PubMed Link to Article
Roth  JDTrevaskis  JLWilson  J  et al.  Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats. Int J Obes (Lond) 2008;32 (8) 1201- 1210
PubMed Link to Article
Aronne  LJHalseth  ABurns  CPorter  LShen  L Enhanced weight loss following co-administration of pramlintide with sibutramine or phentermine in obese subjects [abstract No. 99-OR]. Diabetes 2008;57 ((suppl 1)) A30- A31
Berthoud  HR Homeostatic and non-homeostatic pathways involved in the control of food intake and energy balance. Obesity (Silver Spring) 2006;14 ((suppl 5)) 197S- 200S
PubMed Link to Article
Laugero  KDGomez  FManalo  SDallman  MF Corticosterone infused intracerebroventricularly inhibits energy storage and stimulates the hypothalamo-pituitary axis in adrenalectomized rats drinking sucrose. Endocrinology 2002;143 (12) 4552- 4562
PubMed Link to Article
Pecoraro  NReyes  FGomez  FBhargava  ADallman  MF Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress. Endocrinology 2004;145 (8) 3754- 3762
PubMed Link to Article
Laugero  KDMack  CHankey  MBaron  AParkes  D Rat amylin prevents stress-related feeding behavior.  Paper presented at: 35th Annual Meeting of the Society for Neuroscience November 14, 2005 Washington, DC
Tryon  MHanania  TCaldarone  BJ  et al.  Anxiolytic and antidepressant actions of the pancreatic β-cell hormone, amylin.  Paper presented at: 36th Annual Meeting of the Society for Neuroscience October 16, 2006 Atlanta, GA
Mack  CMSoares  CLaugero  K  et al.  Therapeutic potential of peptide hormones for the treatment of psychiatric disease.  Paper presented at: 37th Annual Meeting of the Society for Neuroscience November 5, 2007 San Diego, CA
Mack  CRoan  JWilson  JReynolds  JParkes  D Sustained glucose-lowering and gastric-emptying effects of amylin agonism in rats [abstract No. 1454-P]. Diabetes 2007;56 ((suppl 1)) A373
Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Amylin neural circuit key sites and activation pathways in the rat. The area postrema is located outside the blood-brain barrier and contains neurons that are directly activated by peripheral amylin, propagating signals to the adjacent nucleus of the solitary tract, the lateral parabrachial nucleus, and the central nucleus of the amygdala. Lesions in the area postrema abrogate the anorexigenic effects of amylin, as well as amylin-induced c-fos expression in the nucleus of the solitary tract, the lateral parabrachial nucleus, and the central nucleus of the amygdala. While binding is evident in other regions residing within the blood-brain barrier using ex vivo autoradiography, the cognate ligand for these binding sites remains to be elucidated. Effects of amylin-dependent neuronal activation include reduced hunger signals, modulation of fasting-induced lateral hypothalamic activation, augmentation of leptin signaling in the ventromedial nucleus of the hypothalamus, and potential antianxiolytic properties.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Direct and Indirect Effects of Amylin Receptor Agonism

References

Pullman  JDarsow  TFrias  JP Pramlintide in the management of insulin-using patients with type 2 and type 1 diabetes. Vasc Health Risk Manag 2006;2 (3) 203- 212
PubMed Link to Article
Smith  SRAronne  LJBurns  CMKesty  NCHalseth  AEWeyer  C Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care 2008;31 (9) 1816- 1823
PubMed Link to Article
Roth  JDRoland  BLCole  RL  et al.  Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci U S A 2008;105 (20) 7257- 7262
PubMed Link to Article
Lutz  TADel Prete  EScharrer  E Reduction of food intake in rats by intraperitoneal injection of low doses of amylin. Physiol Behav 1994;55 (5) 891- 895
PubMed Link to Article
Young  AAGedulin  BVine  WPercy  ARink  TJ Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin. Diabetologia 1995;38 (6) 642- 648
PubMed Link to Article
Silvestre  RARodríguez-Gallardo  JJodka  C  et al.  Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas. Am J Physiol Endocrinol Metab 2001;280 (3) E443- E449Accessed December 6, 2008
PubMed
Young  A Receptor pharmacology. Adv Pharmacol 2005;5247- 65
PubMed
Price  CJHoyda  TDFerguson  AV The area postrema: a brain monitor and integrator of systemic autonomic state. Neuroscientist 2008;14 (2) 182- 194
PubMed Link to Article
Riediger  TSchmid  HALutz  TASimon  E Amylin and glucose co-activate area postrema neurons of the rat. Neurosci Lett 2002;328 (2) 121- 124
PubMed Link to Article
Lutz  TASenn  MAlthaus  JDel Prete  EEhrensperger  FScharrer  E Lesion of the area postrema nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene–related peptide (CGRP) in rats. Peptides 1998;19 (2) 309- 317
PubMed Link to Article
Edwards  GLGedulin  BRJodka  CDilts  RPMiller  CCYoung  A Area postrema (AP)–lesions block the regulation of gastric emptying by amylin [abstract]. Neurogastroenterol Motil 1998;10 (4) 26
Riediger  TZuend  DBecskei  CLutz  TA The anorectic hormone amylin contributes to feeding-related changes of neuronal activity in key structures of the gut-brain axis. Am J Physiol Regul Integr Comp Physiol 2004;286 (1) R114- R122
PubMed Link to Article
Gedulin  BRJodka  CMHerrmann  KYoung  AA Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187. Regul Pept 2006;137 (3) 121- 127
PubMed Link to Article
Block  CHHoffman  GKapp  BS Peptide-containing pathways from the parabrachial complex to the central nucleus of the amygdala. Peptides 1989;10 (2) 465- 471
PubMed Link to Article
Rowland  NERichmond  RM Area postrema and the anorectic actions of dexfenfluramine and amylin. Brain Res 1999;820 (1-2) 86- 91
PubMed Link to Article
Becskei  CGrabler  VEdwards  GLRiediger  TLutz  TA Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK. Brain Res 2007;116276- 84
PubMed Link to Article
Barth  SWRiediger  TLutz  TARechkemmer  G Differential effects of amylin and salmon calcitonin on neuropeptide gene expression in the lateral hypothalamic area and the arcuate nucleus of the rat. Neurosci Lett 2003;341 (2) 131- 134
PubMed Link to Article
Sexton  PMPaxinos  GKenney  MAWookey  PJBeaumont  K In vitro autoradiographic localization of amylin binding sites in rat brain. Neuroscience 1994;62 (2) 553- 567
PubMed Link to Article
Mollet  AMeier  SRiediger  TLutz  TA Histamine H1 receptors in the ventromedial hypothalamus mediate the anorectic action of the pancreatic hormone amylin. Peptides 2003;24 (1) 155- 158
PubMed Link to Article
Osto  MWielinga  PYAlder  BWalser  NLutz  TA Modulation of the satiating effect of amylin by central ghrelin, leptin and insulin. Physiol Behav 2007;91 (5) 566- 572
PubMed Link to Article
Roth  JDHughes  HKendall  EBaron  ADAnderson  CM Antiobesity effects of the β-cell hormone amylin in diet-induced obese rats: effects on food intake, body weight, composition, energy expenditure, and gene expression. Endocrinology 2006;147 (12) 5855- 5864
PubMed Link to Article
Kelley  AEBaldo  BAPratt  WEWill  MJ Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. Physiol Behav 2005;86 (5) 773- 795
PubMed Link to Article
Mack  CWilson  JAthanacio  J  et al.  Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference and body weight. Am J Physiol Regul Integr Comp Physiol 2007;293 (5) R1855- R1863
PubMed Link to Article
Young  A Inhibition of food intake. Adv Pharmacol 2005;5279- 98
PubMed
Roth  JDHughes  HCoffey  TMaier  HTrevaskis  JLAnderson  CM Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat–fed female rats. Am J Physiol Endocrinol Metab 2007;293 (4) E1112- E1117
PubMed Link to Article
Aronne  LFujioka  KAroda  V  et al.  Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab 2007;92 (8) 2977- 2983
PubMed Link to Article
Smith  SRBlundell  JEBurns  C  et al.  Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study. Am J Physiol Endocrinol Metab 2007;293 (2) E620- E627Accessed December 6, 2008
PubMed Link to Article
Chen  HCRoth  JDSchroeder  BEWeyer  C Role of islet-, gut-, and adipocyte-derived hormones in the central control of food intake and body weight: implications for an integrated neurohormonal approach to obesity pharmacotherapy. Curr Diabetes Rev 2008;4 (2) 79- 91
PubMed Link to Article
Trevaskis  JLCoffey  TCole  R  et al.  Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms. Endocrinology 2008;149 (11) 5679- 5687
PubMed Link to Article
Roth  JDTrevaskis  JLWilson  J  et al.  Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats. Int J Obes (Lond) 2008;32 (8) 1201- 1210
PubMed Link to Article
Aronne  LJHalseth  ABurns  CPorter  LShen  L Enhanced weight loss following co-administration of pramlintide with sibutramine or phentermine in obese subjects [abstract No. 99-OR]. Diabetes 2008;57 ((suppl 1)) A30- A31
Berthoud  HR Homeostatic and non-homeostatic pathways involved in the control of food intake and energy balance. Obesity (Silver Spring) 2006;14 ((suppl 5)) 197S- 200S
PubMed Link to Article
Laugero  KDGomez  FManalo  SDallman  MF Corticosterone infused intracerebroventricularly inhibits energy storage and stimulates the hypothalamo-pituitary axis in adrenalectomized rats drinking sucrose. Endocrinology 2002;143 (12) 4552- 4562
PubMed Link to Article
Pecoraro  NReyes  FGomez  FBhargava  ADallman  MF Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress. Endocrinology 2004;145 (8) 3754- 3762
PubMed Link to Article
Laugero  KDMack  CHankey  MBaron  AParkes  D Rat amylin prevents stress-related feeding behavior.  Paper presented at: 35th Annual Meeting of the Society for Neuroscience November 14, 2005 Washington, DC
Tryon  MHanania  TCaldarone  BJ  et al.  Anxiolytic and antidepressant actions of the pancreatic β-cell hormone, amylin.  Paper presented at: 36th Annual Meeting of the Society for Neuroscience October 16, 2006 Atlanta, GA
Mack  CMSoares  CLaugero  K  et al.  Therapeutic potential of peptide hormones for the treatment of psychiatric disease.  Paper presented at: 37th Annual Meeting of the Society for Neuroscience November 5, 2007 San Diego, CA
Mack  CRoan  JWilson  JReynolds  JParkes  D Sustained glucose-lowering and gastric-emptying effects of amylin agonism in rats [abstract No. 1454-P]. Diabetes 2007;56 ((suppl 1)) A373
Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles