Understanding melanocortin-4 receptor control of neuronal circuits: Toward novel therapeutics for obesity syndrome

Ju, Sang Hyeon; Cho, Gyu-Bon; Sohn, Jong Woo

doi:10.1016/j.phrs.2018.01.004

Cited by 28 publications

(17 citation statements)

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“…The melanocortin‐4 receptor is one of the most well‐validated drug targets for the treatment of obesity. However, many peptide and small molecule drugs targeting MC4R have failed in clinical trials as a result of a target‐mediated increase in blood pressure . The growing interest in biased signalling in GPCR drug discovery highlights the urgency to explore novel signalling pathways when considering target‐specific therapeutics .…”

Section: Discussionmentioning

confidence: 99%

“…However, many peptide and small molecule drugs targeting MC4R have failed in clinical trials as a result of a target-mediated increase in blood pressure. [26][27][28] The growing interest in biased signalling in GPCR drug discovery highlights the urgency to explore novel signalling pathways when considering target-specific therapeutics. [32][33][34][35][36] Interestingly, a subset of MC4R mutations in humans is associated with the development of obesity, yet these have been reported to couple normally to Gα s .…”

Section: Discussionmentioning

confidence: 99%

“…Beyond simply elucidating the signalling mechanism(s) of a receptor critical to energy homeostasis, further investigation of this receptor is needed to advance attempts to develop small molecule therapeutics at this receptor, given the finding of a target‐mediated pressor response . A more detailed pharmacological model of receptor signalling, for example, may allow for the development of biased agonists that stimulate weight loss but not the pressor response.…”

Section: Introductionmentioning

confidence: 99%

“…25 Beyond simply elucidating the signalling mechanism(s) of a receptor critical to energy homeostasis, further investigation of this receptor is needed to advance attempts to develop small molecule therapeutics at this receptor, given the finding of a target-mediated pressor response. [26][27][28] A more detailed pharmacological model of receptor signalling, for example, may allow for the development of biased agonists that stimulate weight loss but not the pressor response. To better understand essential functional features of the MC4R that have not yet been elucidated, we aimed to identify potential biochemical and/or pharmacological defects in class V obesity-associated MC4R mutations reported to have normal cell surface expression, ligand binding and coupling to Gα s .…”

Section: Introductionmentioning

confidence: 99%

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Obesity‐associated mutant melanocortin‐4 receptors with normal Gα_s coupling frequently exhibit other discoverable pharmacological and biochemical defects

Gillyard

Fowler

Williams

et al. 2019

J Neuroendocrinology

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Mutations in the melanocortin‐4 receptor (MC4R) are the most common cause of early syndromic obesity known. Most of these mutations result in a loss of protein expression, α‐melanocyte‐stimulating hormone binding, receptor trafficking or coupling to the stimulatory G‐protein, Gαs. However, approximately 26% of the obesity‐associated mutations characterised to date exhibit none of these pharmacological defects. In the present study, we investigated seven of these apparently normal mutant MC4R in more detail and found that the majority (five of the seven) exhibit marked defects including defective binding of another endogenous melanocortin ligand, defective glycosylation, and defective recruitment of β‐arrestin. These data provide support for two hypotheses: (i) that the majority of these rare, obesity‐associated mutations are likely defective and causative of obesity and (ii) that β‐arrestin recruitment is a valuable marker of normal MC4R function. Recent work has demonstrated a statistical correlation between the efficacy of β‐arrestin recruitment to the MC4R and body mass index; however, the data reported here demonstrate both decreased and increased β‐arrestin signalling in obesity‐associated MC4R mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Obesity‐associated mutant melanocortin‐4 receptors with normal Gα_s coupling frequently exhibit other discoverable pharmacological and biochemical defects

Gillyard

Fowler

Williams

et al. 2019

J Neuroendocrinology

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“…Recently, it has been discovered that it is possible to change the conformation of GPCRs by intracellular delivery of agonists and antagonists (Conn & Ulloa-Aguirre 2011). Many MC4R variants linked to obesity in humans have defective function because they are retained intracellularly (Ho & MacKenzie 1999, Lubrano-Berthelier et al 2003, Nijenhuis et al 2003, Tao & Segaloff 2003, Ju et al 2018. Intracellular retention of obesity-linked MC4R variants is dependent on their localization to the ER as misfolded, ubiquitinated proteins (Granell et al 2010, Rene et al 2010.…”

Section: Pharmacological Chaperones and Folding Of Mc4rmentioning

confidence: 99%

The melanocortin pathway and control of appetite-progress and therapeutic implications

Baldini

Phelan

2019

Journal of Endocrinology

185

125

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The initial discovery thatob/obmice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

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An Improved Synthesis of Compound 11, a Unique Bicyclic Melanocortin‐3 Antagonist

Joy,

Dahir,

Cone

et al. 2024

Peptide Science

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The melanocortin‐3 receptor (MC3R) is a G‐protein coupled receptor that regulates appetite and is a potential therapeutic target for anorexia and weight loss treatments. The report of a highly selective synthetic antagonist of MC3R, Cpd11, represents a major advance toward therapeutic targeting of MC3R. However, Cpd11 is challenging to access synthetically, severely limiting its use and additional structural optimization. Here, we outline an improved synthesis of Cpd11 that addresses three major synthetic challenges, including the formation of Cpd11's structurally unique bicyclic core. With these changes, Cpd11 was readily produced (2.3 mg from a 0.05 mmol scale versus ≪ 0.1 mg using the original synthetic methodology) and utilized in MC3R studies in C57BL/6J male mice. Thus, this new approach will increase the accessibility of Cpd11 and is translatable to related bicyclic agonists and antagonists for other melanocortin receptors and may have general applicability toward the synthesis of other multicyclic poly‐cysteine peptides.

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Understanding melanocortin-4 receptor control of neuronal circuits: Toward novel therapeutics for obesity syndrome

Cited by 28 publications

References 100 publications

Obesity‐associated mutant melanocortin‐4 receptors with normal Gα_s coupling frequently exhibit other discoverable pharmacological and biochemical defects

Obesity‐associated mutant melanocortin‐4 receptors with normal Gα_s coupling frequently exhibit other discoverable pharmacological and biochemical defects

The melanocortin pathway and control of appetite-progress and therapeutic implications

An Improved Synthesis of Compound 11, a Unique Bicyclic Melanocortin‐3 Antagonist

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Understanding melanocortin-4 receptor control of neuronal circuits: Toward novel therapeutics for obesity syndrome

Cited by 28 publications

References 100 publications

Obesity‐associated mutant melanocortin‐4 receptors with normal Gαs coupling frequently exhibit other discoverable pharmacological and biochemical defects

Obesity‐associated mutant melanocortin‐4 receptors with normal Gαs coupling frequently exhibit other discoverable pharmacological and biochemical defects

The melanocortin pathway and control of appetite-progress and therapeutic implications

An Improved Synthesis of Compound 11, a Unique Bicyclic Melanocortin‐3 Antagonist

Contact Info

Product

Resources

About

Obesity‐associated mutant melanocortin‐4 receptors with normal Gα_s coupling frequently exhibit other discoverable pharmacological and biochemical defects

Obesity‐associated mutant melanocortin‐4 receptors with normal Gα_s coupling frequently exhibit other discoverable pharmacological and biochemical defects