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Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant

OBJECTIVE: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin–stimulating hormone (α-MSH) and desacetyl-α-melanoc...

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Autores principales: van der Valk, Eline S, Kleinendorst, Lotte, Delhanty, Patric J D, van der Voorn, Bibian, Visser, Jenny A, van Haelst, M M, de Graaff, Laura C G, Huisman, Martin, White, Anne, Ito, Shosuke, Wakamatsu, Kazumasa, de Rijke, Yolanda B, van den Akker, Erica L T, Iyer, Anand M, van Rossum, Elisabeth F C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9797039/
https://www.ncbi.nlm.nih.gov/pubmed/35737586
http://dx.doi.org/10.1210/clinem/dgac342
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author van der Valk, Eline S
Kleinendorst, Lotte
Delhanty, Patric J D
van der Voorn, Bibian
Visser, Jenny A
van Haelst, M M
de Graaff, Laura C G
Huisman, Martin
White, Anne
Ito, Shosuke
Wakamatsu, Kazumasa
de Rijke, Yolanda B
van den Akker, Erica L T
Iyer, Anand M
van Rossum, Elisabeth F C
author_facet van der Valk, Eline S
Kleinendorst, Lotte
Delhanty, Patric J D
van der Voorn, Bibian
Visser, Jenny A
van Haelst, M M
de Graaff, Laura C G
Huisman, Martin
White, Anne
Ito, Shosuke
Wakamatsu, Kazumasa
de Rijke, Yolanda B
van den Akker, Erica L T
Iyer, Anand M
van Rossum, Elisabeth F C
author_sort van der Valk, Eline S
collection PubMed
description OBJECTIVE: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin–stimulating hormone (α-MSH) and desacetyl-α-melanocortin–stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. METHODS: We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. RESULTS: The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. CONCLUSION: The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control.
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spelling pubmed-97970392023-01-03 Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant van der Valk, Eline S Kleinendorst, Lotte Delhanty, Patric J D van der Voorn, Bibian Visser, Jenny A van Haelst, M M de Graaff, Laura C G Huisman, Martin White, Anne Ito, Shosuke Wakamatsu, Kazumasa de Rijke, Yolanda B van den Akker, Erica L T Iyer, Anand M van Rossum, Elisabeth F C J Clin Endocrinol Metab Online Only Articles OBJECTIVE: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin–stimulating hormone (α-MSH) and desacetyl-α-melanocortin–stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. METHODS: We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. RESULTS: The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. CONCLUSION: The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control. Oxford University Press 2022-06-23 /pmc/articles/PMC9797039/ /pubmed/35737586 http://dx.doi.org/10.1210/clinem/dgac342 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Online Only Articles
van der Valk, Eline S
Kleinendorst, Lotte
Delhanty, Patric J D
van der Voorn, Bibian
Visser, Jenny A
van Haelst, M M
de Graaff, Laura C G
Huisman, Martin
White, Anne
Ito, Shosuke
Wakamatsu, Kazumasa
de Rijke, Yolanda B
van den Akker, Erica L T
Iyer, Anand M
van Rossum, Elisabeth F C
Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
title Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
title_full Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
title_fullStr Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
title_full_unstemmed Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
title_short Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
title_sort obesity and hyperphagia with increased defective acth: a novel pomc variant
topic Online Only Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9797039/
https://www.ncbi.nlm.nih.gov/pubmed/35737586
http://dx.doi.org/10.1210/clinem/dgac342
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