A unique MC4R signaling profile for obesity-associated constitutively active variants

in Journal of Molecular Endocrinology
Authors:
Rikus BothaR Botha, Physiology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand

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Shree Senthil KumarS Kumar, Physiology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand

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Natasha L GrimseyN Grimsey, Pharmacology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand

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Kathleen Grace MountjoyK Mountjoy, Physiology, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand

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Correspondence: Kathleen Mountjoy, Email: kmountjoy@auckland.ac.nz
DOI:
https://doi.org/10.1530/JME-23-0008
Volume/Issue:
Accepted Manuscripts
Article Type:
Research Article
Article ID:
JME-23-0008
Online Publication Date:
01 Apr 2023
Copyright:
© 2023 The authors 2023
Open access

The human melanocortin-4 receptor plays a critical role regulating energy homeostasis. Studies on obesogenic hMC4R variants have not yet revealed how human melanocortin-4 receptor maintains body weight. Here, we identified a signaling profile for obesogenic constitutively active H76R and L250Q human melanocortin-4 receptor variants transfected in HEK293 cells that included constitutive activity for adenylyl cyclase, cyclic adenosine monophosphate response element-driven transcription, and calcium mobilization, but not phosphorylated extracellular signal-regulated kinase 1/2 activity. Importantly, the signaling profile included impaired α-melanocyte-stimulating-hormone-induced cyclic adenosine monophosphate response element-driven transcription, but not impaired α-melanocyte-stimulating-hormone-induced adenylyl cyclase, calcium, or phosphorylated extracellular signal-regulated kinase 1/2. This profile was not observed for transfected H158R, a constitutively active human melanocortin-4 receptor variant associated with overweight, but not obesity. We concluded that there is potential for α-melanocyte-stimulating-hormone-induced cyclic adenosine monophosphate response element-driven transcription in HEK293 cells transfected with obesogenic human melanocortin-4 receptor variants to be the key predictive tool for determining whether they exhibit loss-of-function. Furthermore, in vivo α-melanocyte-stimulating-hormone-induced human melanocortin-4 receptor cyclic adenosine monophosphate response element-driven transcription may be key for maintaining body weight.

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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© 2023 The authors 2023
Article ID:
JME-23-0008
Article Type:
Research Article
Received Date:
09 Jan 2023
Rev-recd:
08 Mar 2023
Accepted Date:
11 Apr 2023
Print Publication Date:
Apr 2023
Online Publication Date:
01 Apr 2023