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Metabolic and neurogenic effects of amylin in the rodent area postrema


Liberini, Claudia G. Metabolic and neurogenic effects of amylin in the rodent area postrema. 2016, University of Zurich, Faculty of Science.

Abstract

Amylin, also known as islet amyloid polypeptide, is co-secreted with insulin by pancreatic β-cells in response to nutrient stimuli. Amylin reduces food intake and body weight and also acts as adiposity signal to control energy expenditure (EE). Circulating amylin acts centrally by primarily activating neurons of the area postrema (AP), a circumventricular organ (CVO) located in the hindbrain. Amylin receptors (AMYs) are dimers of the calcitonin-like receptor isoform a (CTRa) and of one member of the receptor activity modifying proteins (RAMPs). The presence of CTRa and the RAMPs has been described in several brain areas, including the AP. Amylin synergistically interacts with the adipokine leptin to reduce food intake and body weight. Although, brain areas where this interaction occurs have not been identified yet, the AP recently emerged as a good candidate. However, evidence of co-expression of all the subunits of the AMYs and leptin receptors (LepRb) in individual AP-neurons is still lacking. Therefore we applied a combination of laser capture microdissection and single-cell qPCR to investigate the co-expression of
AMYs components and LepRb in individual AP-neurons. Our results demonstrated that CTRa and one or more RAMPs transcripts are co-expressed in single APneurons. Moreover, acute amylin treatment differentially regulates its own receptor: while CTRa is un-affected, RAMP1 and RAMP3 mRNAs are consistently downregulated.
On the contrary, RAMP2 mRNA is up-regulated. Furthermore, 30% of Lamylin-activated AP-neurons, which co-express all the transcripts necessary to generate a functional AMY, also co-express LepRb mRNA.

Interestingly, these results outline the possibility that more than one RAMP can be coexpressed with CTRa, raising the question whether different CTRa/RAMPs might mediate different physiological effects in the feeding behavior. Indeed, not only does RAMP1 generate an AMY1 by coupling with CTR, but it also has the potential to bind to the calcitonin-like receptor and generate a calcitonin-gene-related peptide receptor (CGRP). Since both amylin and CGRP decrease food intake and body weight we speculate that RAMP1 might exert a critical role in the regulation of energy balance. In fact, transgenic mice expressing the human (h) RAMP1 (Nestin/hRAMP1) on a regular diet are characterized by a markedly lean phenotype. This suggests that RAMP1 might exert a protective effect against obesity. To further validate this hypothesis, we challenged the transgenic mice with high-fat diet (HFD). Our findings
revealed that the lean phenotype is maintained on HFD and the reduction in body weight results from increased energy expenditure rather than from a reduction in food intake. Hence, RAMP1 appears to be involved in the regulation of energy balance.

Finally, CVOs, such as the AP, have emerged as new neurogenic niches in the adult brain, and amylin has been recently shown to exert a neurotrophic effect. Therefore, we combined transcriptome analysis and immunohistochemical techniques to investigated acute and chronic effects of amylin treatment on the AP of adult rats. Our results showed that acute amylin regulates genes involved in multiple pathways and processes of adult neurogenesis. Moreover, chronic amylin infusion increases the number of newly proliferating cells in the adult AP, and determines the fatecommitment of these adult-born cells into mature neurons rather than glia.

In summary, we demonstrated that all the AMY subunits and the LepRb are coexpressed in single AP-neurons. Acute amylin administration differentially regulates the transcripts of the RAMPs and the LepRb in the AP. Additionally, acute amylin affects genes involved in the regulation of multiple pathways and processes of adult
neurogenesis. Chronic amylin treatment increases the number of newly proliferating cells in the AP and determines their neuronal fate over glia. Thus, amylin, in addition to its role as a satiating hormone, plays a novel role in the regulation of neurogenic processes in the AP of adult rats.

Abstract

Amylin, also known as islet amyloid polypeptide, is co-secreted with insulin by pancreatic β-cells in response to nutrient stimuli. Amylin reduces food intake and body weight and also acts as adiposity signal to control energy expenditure (EE). Circulating amylin acts centrally by primarily activating neurons of the area postrema (AP), a circumventricular organ (CVO) located in the hindbrain. Amylin receptors (AMYs) are dimers of the calcitonin-like receptor isoform a (CTRa) and of one member of the receptor activity modifying proteins (RAMPs). The presence of CTRa and the RAMPs has been described in several brain areas, including the AP. Amylin synergistically interacts with the adipokine leptin to reduce food intake and body weight. Although, brain areas where this interaction occurs have not been identified yet, the AP recently emerged as a good candidate. However, evidence of co-expression of all the subunits of the AMYs and leptin receptors (LepRb) in individual AP-neurons is still lacking. Therefore we applied a combination of laser capture microdissection and single-cell qPCR to investigate the co-expression of
AMYs components and LepRb in individual AP-neurons. Our results demonstrated that CTRa and one or more RAMPs transcripts are co-expressed in single APneurons. Moreover, acute amylin treatment differentially regulates its own receptor: while CTRa is un-affected, RAMP1 and RAMP3 mRNAs are consistently downregulated.
On the contrary, RAMP2 mRNA is up-regulated. Furthermore, 30% of Lamylin-activated AP-neurons, which co-express all the transcripts necessary to generate a functional AMY, also co-express LepRb mRNA.

Interestingly, these results outline the possibility that more than one RAMP can be coexpressed with CTRa, raising the question whether different CTRa/RAMPs might mediate different physiological effects in the feeding behavior. Indeed, not only does RAMP1 generate an AMY1 by coupling with CTR, but it also has the potential to bind to the calcitonin-like receptor and generate a calcitonin-gene-related peptide receptor (CGRP). Since both amylin and CGRP decrease food intake and body weight we speculate that RAMP1 might exert a critical role in the regulation of energy balance. In fact, transgenic mice expressing the human (h) RAMP1 (Nestin/hRAMP1) on a regular diet are characterized by a markedly lean phenotype. This suggests that RAMP1 might exert a protective effect against obesity. To further validate this hypothesis, we challenged the transgenic mice with high-fat diet (HFD). Our findings
revealed that the lean phenotype is maintained on HFD and the reduction in body weight results from increased energy expenditure rather than from a reduction in food intake. Hence, RAMP1 appears to be involved in the regulation of energy balance.

Finally, CVOs, such as the AP, have emerged as new neurogenic niches in the adult brain, and amylin has been recently shown to exert a neurotrophic effect. Therefore, we combined transcriptome analysis and immunohistochemical techniques to investigated acute and chronic effects of amylin treatment on the AP of adult rats. Our results showed that acute amylin regulates genes involved in multiple pathways and processes of adult neurogenesis. Moreover, chronic amylin infusion increases the number of newly proliferating cells in the adult AP, and determines the fatecommitment of these adult-born cells into mature neurons rather than glia.

In summary, we demonstrated that all the AMY subunits and the LepRb are coexpressed in single AP-neurons. Acute amylin administration differentially regulates the transcripts of the RAMPs and the LepRb in the AP. Additionally, acute amylin affects genes involved in the regulation of multiple pathways and processes of adult
neurogenesis. Chronic amylin treatment increases the number of newly proliferating cells in the AP and determines their neuronal fate over glia. Thus, amylin, in addition to its role as a satiating hormone, plays a novel role in the regulation of neurogenic processes in the AP of adult rats.

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Additional indexing

Item Type:Dissertation
Referees:Lutz Thomas A, Gassmann M, Levin Barry E, Boyle Christina N
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2016
Deposited On:23 Jan 2017 16:51
Last Modified:23 Jan 2017 16:51
Number of Pages:131
Related URLs:http://www.recherche-portal.ch/ZAD:default_scope:ebi01_prod010723662 (Library Catalogue)

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