Brainstem mechanisms of amylin-induced anorexia
Introduction
Amylin, also known as islet amyloid polypeptide (IAPP), is a 37 amino acid peptide from the calcitonin gene related peptide family [1]. Amylin is co-secreted with insulin by pancreatic β-cells in response to nutrient ingestion at a ratio of about 1:100 (amylin:insulin) [2], [3]. Amylin has a short half-life of about 15 min in blood circulation [4].
In rats, food intake (e.g. a 5 g test meal given to overnight fasted rats) results in a rapid increase in the endogenous plasma amylin concentration from a fasting level of approximately 3 pmol/l to postprandial levels of about 15–20 pmol/l measured in aortal blood [5]. This increase in plasma amylin was shown to correlate with the size of the respective meal [5]. Acute intraperitoneal (IP) injections of 1–100 µg/kg amylin decrease eating in rats within a few minutes, and dose-dependently reduce meal size without producing signs of visceral illness [6], [7], [8]. Intravenous (3–4 h: 600–2000 pmol kg− 1 min− 1) and intra-area postrema (30 µg over 3 h) administration of the amylin receptor antagonist AC187, at doses that block the eating-inhibitory effect of exogenous amylin, stimulates eating by increasing meal size [9], [10]. The lowest dose of exogenous amylin able to produce a significant reduction in feeding yields plasma amylin levels which are only slightly higher than the concentrations measured postprandially [5], [11]. For these and other reasons, it is generally believed that amylin fulfils the criteria of a physiological signal of satiation [12], [13]. This action seems to be primarily mediated by the area postrema (AP) in the hindbrain (see Section 2 below).
Chronic amylin administration via minipump (2 µg/kg/h, IP) leads to a sustained reduction in food intake due to a decrease in average meal size which is not compensated by an increase in meal frequency [14]. Subsequently, chronic amylin leads to a reduction in body weight gain in rats [7], [14]. These findings reported in laboratory rodents have corresponding effects under clinical conditions in humans. The amylin analogue pramlintide (120–240 µg, 3 times/day) causes weight loss in obese subjects starting 2 weeks after the onset of treatment; this weight loss is accompanied by sustained reductions in portion size, in 24 h-food intake, and also in binge eating tendencies [15], [16]. Long term treatment for 16 weeks resulted in a marked reduction in body weight that remained significantly lower even 8 weeks after treatment cessation [15].
The role of endogenous amylin in the control of eating has also been investigated using amylin knockout (KO) mice. Most studies using these mice showed no difference in adult (≥ 4 months) body weight compared with wildtype (WT) animals [17], [18], [19]. However, amylin KO mice showed a higher rate of body weight gain than WT controls, between one and about 4 months of age [18], [20]. Average food intake in amylin KO mice was shown to be slightly though not significantly higher than in WT animals during this time window, but food intake was only measured on specific days (about once weekly), and not throughout the entire period from weaning to 4 months of age [19], [21].
Rats transgenic for the overexpression of human amylin had a slightly lower body weight than WT controls [22]. This is in principle consistent with the reported effects of exogenous amylin on eating and body weight gain, but food intake in these rats was not measured systematically.
Amylin seems to exert additional effects at physiological plasma concentrations, such as inhibition of gastric emptying, glucagon secretion, and of gastric acid and digestive enzyme secretion [12], [21]. The former two effects are the basis for the use of pramlintide in co-therapy with insulin in diabetic humans because it improves blood glucose profiles in type 1 and type 2 diabetes mellitus patients [23], [24]. From the above mentioned actions, the AP was shown to mediate amylin's action to inhibit gastric emptying, eventually involving vagal efferents [25], [26]. The site(s) of action for the other effects still need further investigation.
Both acute and chronic administration of amylin and of the amylin receptor agonist salmon calcitonin (sCT) increase energy expenditure, as assessed by indirect calorimetry [7], [27], [28], [29], [30]. For a review on the effects of exogenous amylin on energy expenditure see [31]. The physiological role of amylin's effect on energy expenditure and the exact site of action are still unclear. One of our own unpublished studies suggests that this effect may also be mediated by the AP because direct low dose amylin or sCT infusions into the AP increased energy expenditure and body temperature, but these findings still require confirmation. Several lines of evidence indicate that amylin may also share characteristics of adiposity signals, such as leptin or insulin. This aspect of amylin action is extensively covered in a recent review [32]. It is not clear whether the same hindbrain neuromechanisms involved in amylin's satiating effect are involved in that latter aspect of amylin action.
Section snippets
Amylin site of action at the brainstem
The AP is one of several brain regions that show strong amylin binding in amylin receptor autoradiography studies [33]. The anorectic effect of amylin seems to be mediated by a direct humoral action on neurons in the AP [14], [34] which lacks a functional blood brain barrier [35]. Here, we list the available structural and functional data indicating that this activation of the AP is necessary and sufficient to bring about amylin's satiating effect.
The amylin receptor, which is expressed in the
Brainstem intracellular mechanisms mediating amylin signaling
Numerous studies investigated the central mechanisms that may mediate amylin's effect on eating. Here, we review specific intracellular signaling molecules in neurons of discrete brain areas that are triggered by the peripheral administration of amylin. These molecules will be briefly described in this section, as well as the potential functional relevance in respect to amylin's effect on eating.
Most studies mapping the brain areas activated by amylin made use of the expression pattern of the
Brainstem neurotransmitter systems mediating amylin anorexia
Recent experiments focused on the phenotype of the neurons mediating amylin's action in the AP. Previous immunohistochemical studies had identified catecholamine and serotonin (5-HT) immunoreactive fibers and cell bodies in the AP and the NTS [63], [64], [65]. The catecholaminergic population of neurons in the AP seems to be mainly noradrenergic [63], [66]. Furthermore, a large number of projections from the AP and NTS to the LPB are noradrenergic [67] or serotoninergic [68]. Interestingly,
Brainstem neuronal pathways involved in amylin signaling
Immunohistochemical studies using the immediate early gene product c-Fos as a marker of neuronal activation helped to identify the central nervous system activation pattern of amylin. Exogenous and endogenous amylin activate the AP–NTS–LPB neuroaxis, but c-Fos was also expressed in the central amygdaloid nucleus (Ce) and the lateral subdivisions of the bed nucleus of the stria terminalis (BSTL) [46], [52]. These brain structures are part of the central gustatory/enteroceptive systems and are
Possible hormone interactions at the brainstem/perspectives
Because of the potential implications of combined hormonal treatment for anti-obesity therapy [95], [96], we will briefly discuss the interaction of amylin with other hormones; particularly the types of interactions that may involve the brainstem.
Most of the brainstem areas expressing c-Fos in response to amylin are also activated by other gastrointestinal peptides that inhibit eating, namely CCK [97], [98], GLP-1 [99] or its receptor agonist exendin-4 [100] and peptide YY 3–36 (PYY) [101].
As
Areas of research
In this review we summarized the current knowledge on the relevance of the brainstem in the mediation of amylin's anorectic action. Obviously, there is still a long list of unanswered or only partly answered questions. These include e.g.: which specific amylin receptor form is expressed in the AP amylin-activated neurons? Is cGMP induced specifically in NA-neurons in the AP? What is the phenotype of the amylin-activated neurons in the AP that do not express NA? Are those neurons also relevant
Concluding remarks
Studies carried out over the last 25 years gathered an extensive array of data on amylin's effect on eating; those findings clearly classify amylin as a physiological satiation signal. The characterization of amylin's site of action, intracellular signaling cascades, neurotransmitters and central pathways mediating amylin's effects on food intake, body weight, and other metabolic effects, has advanced tremendously in recent years. Unlike many other hormones which act primarily via the
Acknowledgements
The financial support of the Swiss National Science Foundation, Novartis Foundation for Medical and Biological Research, and of the Zurich Center of Integrative Human Physiology are gratefully acknowledged. Special thanks to all our present and past collaborators, particularly to Dr. T. Riediger, for their contribution to much of the work presented in this review.
References (109)
- et al.
Dose response characteristics for the hyperglycemic, hyperlactemic, hypotensive and hypocalcemic actions of amylin and calcitonin gene-related peptide-I (CGRP alpha) in the fasted, anaesthetized rat
Life Sci
(1993) - et al.
Amylin decreases meal size in rats
Physiol Behav
(1995) - et al.
Reduction of food intake in rats by intraperitoneal injection of low doses of amylin
Physiol Behav
(1994) - et al.
Infusion of the amylin antagonist AC 187 into the area postrema increases food intake in rats
Physiol Behav
(2004) Amylinergic control of food intake
Physiol Behav
(2006)- et al.
Biological importance of the peptides of the calcitonin family as revealed by disruption and transfer of corresponding genes
Peptides
(2004) - et al.
Endogenous amylin contributes to the anorectic effects of cholecystokinin and bombesin
Peptides
(2003) - et al.
Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin)
Biochem Biophys Res Commun
(1998) - et al.
Chronically administered islet amyloid polypeptide in rats serves as an adiposity inhibitor and regulates energy homeostasis
Pancreatology
(2005) - et al.
Central and peripheral administration of amylin induces energy expenditure in anesthetized rats
Peptides
(2008)
The acute effect of amylin and salmon calcitonin on energy expenditure
Physiol Behav
In vitro autoradiographic localization of amylin binding sites in rat brain
Neuroscience
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
Immunohistochemical mapping of calcitonin receptors in the adult rat brain
Brain Res
Expression of receptor-activity modifying protein (RAMP) mRNAs in the mouse brain
Brain Res Mol Brain Res
Peripheral amylin activates circumventricular organs expressing calcitonin receptor a/b subtypes and receptor-activity modifying proteins in the rat
Brain Res
Subdiaphragmatic vagotomy does not influence the anorectic effect of amylin
Peptides
Dose–response for glucagonostatic effect of amylin in rats
Metabolism
Amylin and glucose co-activate area postrema neurons of the rat
Neurosci Lett
The ability of amylin to reduce eating depends on the protein content of the diet
Appetite
Comparison of Fos induced in rat brain by GLP-1 and amylin
Regul Pept
Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK
Brain Res
Synergy between amylin and cholecystokinin for inhibition of food intake in mice
Physiol Behav
Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals
Neuroscience
Distribution of dopamine, noradrenaline and adrenaline in coronal sections of the rat lower brainstem
Brain Res
A serotonin-containing pathway from the area postrema to the parabrachial nucleus in the rat
Neuroscience
Catecholamine and serotonin colocalization in projection neurons of the area postrema
Brain Res
The role of norepinephrine in the function of the area postrema. I. Immunofluorescent localization of dopamine-beta-hydroxylase and electron microscopy
Brain Res
Noradrenergic neurons of the area postrema mediate amylin's anorectic action
Appetite
Cholecystokinin, dopamine D2 and N-methyl-d-aspartate binding sites in the nucleus of the solitary tract of the rat: possible relationship to ingestive behavior
Neuroscience
The role of norepinephrine in the function of the area postrema. II. In vitro incubation and stimulated release of tritiated norepinephrine
Brain Res
The histaminergic, but not the serotoninergic, system mediates amylin's anorectic effect
Peptides
Histamine H1 receptors in the ventromedial hypothalamus mediate the anorectic action of the pancreatic hormone amylin
Peptides
Area postrema and the anorectic actions of dexfenfluramine and amylin
Brain Res
The central signaling pathways of amylin: a neuroanatomical study
Appetite
Peripheral administration of cholecystokinin activates c-fos expression in the locus coeruleus/subcoeruleus nucleus, dorsal vagal complex and paraventricular nucleus via capsaicin-sensitive vagal afferents and CCK-A receptors in the rat
Brain Res
An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis
Gastroenterology
Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients
Proc Natl Acad Sci U S A
Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans
Diabetes
Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment
J Clin Invest
Amylin reduces food intake in rats at doses that cause only slightly supraphysiological plasma amylin levels
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
Amylin receptor blockade stimulates food intake in rats
Am J Physiol Regul Integr Comp Physiol
Sufficiency of postprandial plasma levels of islet amyloid polypeptide for suppression of feeding in rats
Am J Physiol
Roles of amylin in diabetes and in regulation of nutrient load
Nutrition
The anorectic effect of a chronic peripheral infusion of amylin is abolished in area postrema/nucleus of the solitary tract (AP/NTS) lesioned rats
Int J Obes Relat Metab Disord
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
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
Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo
J Cell Biol
Pancreatic amylin as a centrally acting satiating hormone
Curr Drug Targets
Cited by (75)
The processing intermediate of human amylin, pro-amylin(1–48), has in vivo and in vitro bioactivity
2024, Biophysical ChemistryMucosal and hormonal adaptations after Roux-en-Y gastric bypass
2023, Surgery for Obesity and Related DiseasesAmylin regulates testosterone levels via steroidogenesis-related enzymes in the central nervous system of male mice
2022, NeuropeptidesCitation Excerpt :Additionally, amylin injection (100 μg/kg) significantly reduced the expression of 3β-HSD, CYP17A1, and StAR (Fig. 7), but increased pERK expression (Fig. 8). The activation of AP neurons is likely synaptically transmitted to the forebrain by the neuro-axis comprising NTS and PBN (Potes and Lutz, 2010; Potes et al., 2010). NTS is the primary projection area of vagal and non-vagal afferent nerves that transfer information from the periphery (particularly the abdominal cavity) to the brain.
Creating the amylin story
2022, AppetiteViral depletion of calcitonin receptors in the area postrema: A proof-of-concept study
2020, Physiology and Behavior