Loss of Function of the Melanocortin 2 Receptor Accessory Protein 2 Is Associated with Mammalian Obesity

Asai, Masato; Ramachandrappa, Shwetha; Joachim, Maria; Shen, Yuan Li; Zhang, Rong; Nuthalapati, Nikhil; Ramanathan, Visali; Strochlic, David E.; Ferket, P. R.; Linhart, Kirsten; Ho, Caroline B.; Novoselova, Tatiana V.; Garg, Shivam; Ridderstråle, Martin; Marcus, Claude; Hirschhorn, Joel N.; Keogh, Julia M.; O’Rahilly, Stephen; Chan, Li F.; Clark, Adrian; Farooqi, I. Sadaf; Majzoub, Joseph A.

doi:10.1126/science.1233000

Cited by 243 publications

(373 citation statements)

References 20 publications

(38 reference statements)

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“…As with MRAP, MRAP2 also naturally exists as an antiparallel homodimer but with a distinct tissue expression pattern principally in many areas of the CNS (Chan et al 2009, Asai et al 2013, Chaly et al 2016. We demonstrated that MRAP2 interacted with all five of the melanocortin receptors in transfected cells (as does MRAP1) (Chan et al 2009).…”

Section: Mrap2mentioning

confidence: 81%

“…Asai and coworkers (Asai et al 2013) demonstrated that under certain transfection conditions, in which a 6:1 ratio of MRAP2 to MC4R expression vector was used, MRAP2 reduced the constitutive activity of the MC4R and enhanced the maximal effect of α-MSH stimulation. As this results in a greater change in signal for a given change in agonist dosage, this can be interpreted as 'sensitizing' the MC4R to agonist.…”

Section: Mrap2mentioning

confidence: 99%

“…These contrasts should prompt caution in interpreting heterologous cell transient expression studies, particularly when discrepant concentrations of expression vector are required to demonstrate a result. Arguably, a more physiological examination of this hypothesis is provided by the development of the MRAP2 gene deleted mouse (Mrap2−/−), which exhibited a severe obesity phenotype (Asai et al 2013). A hypomorph Mrap2 mouse generated using a different strategy and only expressing a fraction of normal Mrap2 mRNA resulted in a very similar phenotype (Novoselova et al 2016), as did deletion of Mrap2 exclusively in the Sim1 neurons of the paraventricular nucleus -implying that the mechanism was dependent solely on these neurons in the hypothalamus (Asai et al 2013).…”

Section: F3mentioning

confidence: 99%

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Promiscuity among the MRAPs

Clark

Chan

2017

Journal of Molecular Endocrinology

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The melanocortin 2 receptor accessory protein (MRAP) was originally discovered to be an essential co-receptor for the ACTH receptor/melanocortin 2 receptor, and it physically interacts with this receptor and is required for receptor trafficking and ligand binding. A related molecule, MRAP2, is mainly expressed in the CNS and appears to have a role with the melanocortin 4 receptor. Consistent with this is the observation that a massively obese phenotype develops when the Mrap2 gene is deleted in mice. However, the characteristics of this phenotype differ from those of Mc4r-deleted mice and suggest that an additional role, possibly resulting from an interaction with other receptors is possible. In support of this, a functional interaction with the prokineticin receptors was recently reported. Evidence for other receptor interactions and aspects of the tissue distribution of MRAP and MRAP2 gene expression may indicate that these accessory proteins have a wider role than with the melanocortin receptors alone.

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Section: Mrap2mentioning

confidence: 81%

Section: Mrap2mentioning

confidence: 99%

Section: F3mentioning

confidence: 99%

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Promiscuity among the MRAPs

Clark

Chan

2017

Journal of Molecular Endocrinology

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“…Therefore, MRAP2 does not appear to play a major role in adrenocortical ACTH signalling (Metherell et al 2005). A precise function on MC4R signalling modulation and, consequently, on body weight control, was recently attributed to MRAP2 (Asai et al 2013, Sebag et al 2013. Mrap2 knockout mice are severely obese and weight gain seems to result, in part, from a reduced function of MC4R (Asai et al 2013).…”

Section: Melanocortin System: Receptors Ligands and Accessory Proteinsmentioning

confidence: 99%

“…A precise function on MC4R signalling modulation and, consequently, on body weight control, was recently attributed to MRAP2 (Asai et al 2013, Sebag et al 2013. Mrap2 knockout mice are severely obese and weight gain seems to result, in part, from a reduced function of MC4R (Asai et al 2013). In fact, MRAP2 was found to enhance MC4R signalling in response to a-MSH (Asai et al 2013, Sebag et al 2013, in contrast to the study by Chan et al (2009) that reported a MRAP2 inhibitory effect on MC4R signalling using NDP-a-MSH instead of a-MSH.…”

Section: Melanocortin System: Receptors Ligands and Accessory Proteinsmentioning

confidence: 99%

Structural determinants regulating cell surface targeting of melanocortin receptors

Rodrigues¹,

Sousa

Almeida

et al. 2013

Journal of Molecular Endocrinology

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Melanocortin receptors (MCRs) belong to the G-protein-coupled receptor family of transmembrane proteins. They recognize specific ligands named melanocortins that are mainly produced in the pituitary and hypothalamus. Newly synthesized MCRs at the endoplasmic reticulum are subjected to quality control mechanisms that screen for the correct structure, folding or processing, essential for their proper cell surface expression. Some motifs, located at the N-or C-terminus or even on transmembrane and in loop regions, have been implicated in these biological processes. This article reviews these specific domains and the role of accessory proteins and post-translation modifications in MCRs' targeting to cell surface. Additionally, promising approaches involving pharmacological stabilization of misfolded and misrouted mutant MCRs, which improve their forward transport, are reported. Understanding the MCRs' structural determinants fundamental for their proper cell surface integration is essential for correcting abnormalities found in some diseases.

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Obesity: Genetics

Grant

McCormack

2015

Encyclopedia of Life Sciences

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Obesity is a disorder of energy balance. In obese individuals, there is excess body fat accumulation, which can lead to myriad health problems. The dysregulation of energy intake (appetite) and energy expenditure (activity) in obesity remains incompletely understood, but studies in humans and in model systems clearly demonstrate a strong genetic component to this condition. Within the past decade, major progress has been made in characterising the genetic component of obesity, with genome‐wide association studies revealing the most loci, including identifying the strongest association signal harboured within the FTO gene. Such studies have thus provided greater insight into the aetiology of this complex trait and are aiding in making diagnostic and therapeutic inroads into this common health concern. Key Concepts Obesity is characterised by an accumulation of excess adipose tissue that has myriad adverse health effects in virtually every organ system. The rising global prevalence of obesity, particularly in developing nations and in children, is worrisome and incompletely understood. Despite clear environmental contributions to disease risk, obesity is highly heritable. In so‐called ‘syndromic’ genetic forms of obesity, genetic changes lead to obesity along with involvement of other organ systems. In ‘non‐syndromic’ obesity, genetic changes lead to an obesity‐predominant phenotype. Animal models of these conditions have led to important insights on the hypothalamic control of appetite. Technological advances have led to the ability to perform genome‐wide association studies and identify novel genes and pathways related to obesity. The complex interaction between genetics/epigenetics and myriad factors including the microbiome, diet/environment, physical activity and circadian rhythm may hold clues as to what individualised therapeutics may improve prevention and treatment of this highly morbid condition.

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Loss of Function of the Melanocortin 2 Receptor Accessory Protein 2 Is Associated with Mammalian Obesity

Cited by 243 publications

References 20 publications

Promiscuity among the MRAPs

Promiscuity among the MRAPs

Structural determinants regulating cell surface targeting of melanocortin receptors

Obesity: Genetics

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