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

Eline S Van Der Valk; Lotte Kleinendorst; Patric J D Delhanty; Bibian Van Der Voorn; Jenny A Visser; M M Van Haelst; Laura C G De Graaff; Martin Huisman; Anne White; Shosuke Ito; Kazumasa Wakamatsu; Yolanda B De Rijke; Erica L T Van Den Akker; Anand M Iyer; Elisabeth F C Van Rossum

doi:10.1210/clinem/dgac342

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

Eline S Van Der Valk, Lotte Kleinendorst, Patric J D Delhanty, Bibian Van Der Voorn, Jenny A Visser, M M Van Haelst, Laura C G De Graaff, Martin Huisman, Anne White, Shosuke Ito, Kazumasa Wakamatsu, Yolanda B De Rijke, Erica L T Van Den Akker, Anand M Iyer, Elisabeth F C Van Rossum

Division of Diabetes, Endocrinology & Gastroenterology (L5)

Research output: Contribution to journal › Article › peer-review

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Abstract

Context: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropic hormone (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to alpha-melanocortin stimulating hormone (α-MSH) and desacetyl-alpha-melanocortin stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region, is required for regulating food intake and energy balance.

Case description: We present two sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site. They had obesity, hyperphagia and hypocortisolism, with markedly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism.

Conclusions The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also in humans required for feeding control.

Original language	English
Journal	The Journal of Clinical Endocrinology & Metabolism
Early online date	23 Jun 2022
DOIs	https://doi.org/10.1210/clinem/dgac342
Publication status	Published - 23 Jun 2022

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20220511 revised manuscript POMC casesAccepted author manuscript, 94 KB

https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac342/6614243

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Van Der Valk, E. S., Kleinendorst, L., Delhanty, P. J. D., Van Der Voorn, B., Visser, J. A., Van Haelst, M. M., De Graaff, L. C. G., Huisman, M., White, A., Ito, S., Wakamatsu, K., De Rijke, Y. B., Van Den Akker, E. L. T., Iyer, A. M., & Van Rossum, E. F. C. (2022). Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant. The Journal of Clinical Endocrinology & Metabolism. https://doi.org/10.1210/clinem/dgac342

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title = "Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant",

abstract = "Context: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropic hormone (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to alpha-melanocortin stimulating hormone (α-MSH) and desacetyl-alpha-melanocortin stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region, is required for regulating food intake and energy balance. Case description: We present two sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site. They had obesity, hyperphagia and hypocortisolism, with markedly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. Conclusions The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also in humans required for feeding control.",

author = "{Van Der Valk}, {Eline S} and Lotte Kleinendorst and Delhanty, {Patric J D} and {Van Der Voorn}, Bibian and Visser, {Jenny A} and {Van Haelst}, {M M} and {De Graaff}, {Laura C G} and Martin Huisman and Anne White and Shosuke Ito and Kazumasa Wakamatsu and {De Rijke}, {Yolanda B} and {Van Den Akker}, {Erica L T} and Iyer, {Anand M} and {Van Rossum}, {Elisabeth F C}",

year = "2022",

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doi = "10.1210/clinem/dgac342",

language = "English",

journal = "The Journal of Clinical Endocrinology & Metabolism",

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Van Der Valk, ES, Kleinendorst, L, Delhanty, PJD, Van Der Voorn, B, Visser, JA, Van Haelst, MM, De Graaff, LCG, Huisman, M, White, A, Ito, S, Wakamatsu, K, De Rijke, YB, Van Den Akker, ELT, Iyer, AM & Van Rossum, EFC 2022, 'Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant', The Journal of Clinical Endocrinology & Metabolism. https://doi.org/10.1210/clinem/dgac342

TY - JOUR

T1 - Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant

AU - Van Der Valk, Eline S

AU - Kleinendorst, Lotte

AU - Delhanty, Patric J D

AU - Van Der Voorn, Bibian

AU - Visser, Jenny A

AU - Van Haelst, M M

AU - De Graaff, Laura C G

AU - Huisman, Martin

AU - White, Anne

AU - Ito, Shosuke

AU - Wakamatsu, Kazumasa

AU - De Rijke, Yolanda B

AU - Van Den Akker, Erica L T

AU - Iyer, Anand M

AU - Van Rossum, Elisabeth F C

PY - 2022/6/23

Y1 - 2022/6/23

N2 - Context: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropic hormone (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to alpha-melanocortin stimulating hormone (α-MSH) and desacetyl-alpha-melanocortin stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region, is required for regulating food intake and energy balance. Case description: We present two sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site. They had obesity, hyperphagia and hypocortisolism, with markedly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. Conclusions The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also in humans required for feeding control.

AB - Context: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropic hormone (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to alpha-melanocortin stimulating hormone (α-MSH) and desacetyl-alpha-melanocortin stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region, is required for regulating food intake and energy balance. Case description: We present two sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site. They had obesity, hyperphagia and hypocortisolism, with markedly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. Conclusions The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also in humans required for feeding control.

U2 - 10.1210/clinem/dgac342

DO - 10.1210/clinem/dgac342

M3 - Article

SN - 0021-972X

JO - The Journal of Clinical Endocrinology & Metabolism

JF - The Journal of Clinical Endocrinology & Metabolism

ER -

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

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