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Systemic and Central Amylin, Amylin Receptor Signaling, and Their Physiological and Pathophysiological Roles in Metabolism

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Abstract

This article in the Neural and Endocrine Section of Comprehensive Physiology discusses the physiology and pathophysiology of the pancreatic hormone amylin. Shortly after its discovery in 1986, amylin has been shown to reduce food intake as a satiation signal to limit meal size. Amylin also affects food reward, sensitizes the brain to the catabolic actions of leptin, and may also play a prominent role in the development of certain brain areas that are involved in metabolic control. Amylin may act at different sites in the brain in addition to the area postrema (AP) in the caudal hindbrain. In particular, the sensitizing effect of amylin on leptin action may depend on a direct interaction in the hypothalamus. The concept of central pathways mediating amylin action became more complex after the discovery that amylin is also synthesized in certain hypothalamic areas but the interaction between central and peripheral amylin signaling remains currently unexplored. Amylin may also play a dominant pathophysiological role that is associated with the aggregation of monomeric amylin into larger, cytotoxic molecular entities. This aggregation in certain species may contribute to the development of type 2 diabetes mellitus but also cardiovascular disease. Amylin receptor pharmacology is complex because several distinct amylin receptor subtypes have been described, because other neuropeptides [e.g., calcitonin gene‐related peptide (CGRP)] can also bind to amylin receptors, and because some components of the functional amylin receptor are also used for other G‐protein coupled receptor (GPCR) systems. © 2020 American Physiological Society. Compr Physiol 10:811‐837, 2020.

Figure 1. Figure 1. (A) Pancreatic islet of a Wistar rat with immunohistochemical staining for amylin‐positive beta cells (red) and glucagon positive alpha cells (blue); other islet cell types are not specified. The islet is surrounded by exocrine pancreatic tissue (brown‐green). (B) Amylin has the propensity to aggregate into oligomers and mature amyloid fibrils in primates and in cats. The amyloidogenecity is determined by the amino acids 20 to 29 within the amylin molecule. The example shows moderate deposition of mature extracellular amyloid in the pancreatic islet of a 12‐year‐old diabetic cat. Homogenous material stained in light red: mature extracellular amyloid fibrils; islet cells stained in dark red: amylin producing pancreatic beta cells; islet cells stained in light blue: non‐beta cells; pancreatic islet surrounded by exocrine pancreas tissue (in light blue).
Figure 2. Figure 2. (A) Schematic overview of the rat brain with sites of amylin synthesis. Immunohistological stainings indicated amylin synthesis in the subpostremal region (ventral to the area postrema; sub‐AP) in male rats (unpublished data‐ see B). Further, in situ hybridization studies indicated amylin synthesis in the medial preoptic area (MPA) and the medial preoptic nucleus (MPO) of female rats 74. Within the hypothalamus, immunohistochemical stainings indicated amylin synthesis in the hypothalamic paraventricular (PVN) and arcuate nuclei (ARC), in the dorsomedial hypothalamus (DMH) and in the lateral hypothalamus (LH) in mice 145. (B) 3,3′‐Diaminobenzidine (DAB) immunohistochemical staining (mouse anti‐amylin antibody 145, Amylin Pharmaceuticals Inc.) of amylin positive cells (indicated with white arrows) in area subpostrema (ASP) region of 8 weeks old male Sprague‐Dawley rat fed ad libitum. Rats were anesthetized with pentobarbital and perfused with 4% PFA, brain was postfixed in 4% PFA for 24 h, followed by 24 h in 20% sucrose solution.
Figure 3. Figure 3. Three subtypes of the amylin receptor (AMY) have been characterized. These consist of the calcitonin core receptor [CTR (the splice variant CT(a) is the best characterized)] plus one of three receptor activity modifying proteins (RAMP 1‐3). AMY1‐3 is activated by amylin and sCT, AMY1 is also considered the second receptor for calcitonin‐gene related peptide (CGRP). The CTR without RAMPs is the calcitonin receptor which binds calcitonin and salmon calcitonin (sCT) with a much higher affinity than amylin. Font size of the ligands indicates the relative binding affinity at the respective receptor subtypes. Cells carrying the CTR plus more than one RAMP (which are not depicted in the Figure) may express more complex receptor aggregates with so far unknown pharmacology. For details, see text.
Figure 4. Figure 4. Schematic overview of the rat brain with sites of direct and indirect amylin action. The most extensively studied brain areas that are involved in amylin action are the caudal hindbrain with the area postrema (AP) as a primary target, the nucleus of the solitary tract (NTS) and the lateral parabrachial nucleus (LPBN) as AP projection sites. Other brain areas that have been implicated in amylin action are the ventral tegmental area (VTA) which projects to the nucleus accumbens (NAc), and the lateral dorsal tegmental nucleus (LDTg). Various nuclei of the hypothalamus (HT) are also direct or indirect targets for amylin action. For details, see text.
Figure 5. Figure 5. Schematic overview of rat brain sites which may be involved in the functional interaction between amylin and leptin for their combined effects on energy homeostasis. Amylin and leptin coactivate neurons in the area postrema (AP) and amylin increases leptin receptor expression in the AP. Within the hypothalamus, amylin and leptin interact mainly within the ventromedial hypothalamus, including the ventromedial hypothalamic nucleus (VMN), the hypothalamic arcuate (ARC) nucleus, and its projections to the paraventricular (PVN) nuclei. Further, direct interaction has also been suggested in the ventral tegmental area (VTA). For details, see text.


Figure 1. (A) Pancreatic islet of a Wistar rat with immunohistochemical staining for amylin‐positive beta cells (red) and glucagon positive alpha cells (blue); other islet cell types are not specified. The islet is surrounded by exocrine pancreatic tissue (brown‐green). (B) Amylin has the propensity to aggregate into oligomers and mature amyloid fibrils in primates and in cats. The amyloidogenecity is determined by the amino acids 20 to 29 within the amylin molecule. The example shows moderate deposition of mature extracellular amyloid in the pancreatic islet of a 12‐year‐old diabetic cat. Homogenous material stained in light red: mature extracellular amyloid fibrils; islet cells stained in dark red: amylin producing pancreatic beta cells; islet cells stained in light blue: non‐beta cells; pancreatic islet surrounded by exocrine pancreas tissue (in light blue).


Figure 2. (A) Schematic overview of the rat brain with sites of amylin synthesis. Immunohistological stainings indicated amylin synthesis in the subpostremal region (ventral to the area postrema; sub‐AP) in male rats (unpublished data‐ see B). Further, in situ hybridization studies indicated amylin synthesis in the medial preoptic area (MPA) and the medial preoptic nucleus (MPO) of female rats 74. Within the hypothalamus, immunohistochemical stainings indicated amylin synthesis in the hypothalamic paraventricular (PVN) and arcuate nuclei (ARC), in the dorsomedial hypothalamus (DMH) and in the lateral hypothalamus (LH) in mice 145. (B) 3,3′‐Diaminobenzidine (DAB) immunohistochemical staining (mouse anti‐amylin antibody 145, Amylin Pharmaceuticals Inc.) of amylin positive cells (indicated with white arrows) in area subpostrema (ASP) region of 8 weeks old male Sprague‐Dawley rat fed ad libitum. Rats were anesthetized with pentobarbital and perfused with 4% PFA, brain was postfixed in 4% PFA for 24 h, followed by 24 h in 20% sucrose solution.


Figure 3. Three subtypes of the amylin receptor (AMY) have been characterized. These consist of the calcitonin core receptor [CTR (the splice variant CT(a) is the best characterized)] plus one of three receptor activity modifying proteins (RAMP 1‐3). AMY1‐3 is activated by amylin and sCT, AMY1 is also considered the second receptor for calcitonin‐gene related peptide (CGRP). The CTR without RAMPs is the calcitonin receptor which binds calcitonin and salmon calcitonin (sCT) with a much higher affinity than amylin. Font size of the ligands indicates the relative binding affinity at the respective receptor subtypes. Cells carrying the CTR plus more than one RAMP (which are not depicted in the Figure) may express more complex receptor aggregates with so far unknown pharmacology. For details, see text.


Figure 4. Schematic overview of the rat brain with sites of direct and indirect amylin action. The most extensively studied brain areas that are involved in amylin action are the caudal hindbrain with the area postrema (AP) as a primary target, the nucleus of the solitary tract (NTS) and the lateral parabrachial nucleus (LPBN) as AP projection sites. Other brain areas that have been implicated in amylin action are the ventral tegmental area (VTA) which projects to the nucleus accumbens (NAc), and the lateral dorsal tegmental nucleus (LDTg). Various nuclei of the hypothalamus (HT) are also direct or indirect targets for amylin action. For details, see text.


Figure 5. Schematic overview of rat brain sites which may be involved in the functional interaction between amylin and leptin for their combined effects on energy homeostasis. Amylin and leptin coactivate neurons in the area postrema (AP) and amylin increases leptin receptor expression in the AP. Within the hypothalamus, amylin and leptin interact mainly within the ventromedial hypothalamus, including the ventromedial hypothalamic nucleus (VMN), the hypothalamic arcuate (ARC) nucleus, and its projections to the paraventricular (PVN) nuclei. Further, direct interaction has also been suggested in the ventral tegmental area (VTA). For details, see text.
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Christelle Le Foll, Thomas A. Lutz. Systemic and Central Amylin, Amylin Receptor Signaling, and Their Physiological and Pathophysiological Roles in Metabolism. Compr Physiol null, 10: 811-837. doi: 10.1002/cphy.c190034