Elsevier

Physiology & Behavior

Volume 100, Issue 5, 14 July 2010, Pages 511-518
Physiology & Behavior

Brainstem mechanisms of amylin-induced anorexia

https://doi.org/10.1016/j.physbeh.2010.03.001Get rights and content

Abstract

Amylin is secreted by pancreatic beta-cells and is believed to be a physiological signal of satiation. Amylin's effect on eating has been shown to be mediated via a direct action at the area postrema (AP) via amylin receptors that are heterodimers of the calcitonin receptor core protein with a receptor activity modifying protein. Peripheral amylin leads to accumulation of cyclic guanosine monophosphate, phosphorylated extracellular-signal regulated kinase 1/2 and c-Fos protein in AP neurons. The particular amylin-activated AP neurons mediating its anorexigenic action seem to be noradrenergic. The central pathways mediating amylin's effects have been characterized by lesioning and tracing studies, identifying important connections from the AP to the nucleus of the solitary tract and lateral parabrachial nucleus. Amylin was shown to interact, probably at the brainstem, with other signals involved in the short term control of food intake, namely cholecystokinin, glucagon-like peptide 1 and peptide YY. Amylin also interacts with the adiposity signal leptin; this interaction, which is thought to involve the hypothalamus, may have important implications for the development of new and improved hormonal obesity treatments.

In conclusion, amylin actions on food intake seem to reside primarily within the brainstem, and the associated mechanisms are starting to be unraveled.

The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

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.

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