학술논문
Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
Clinical Research Article
Clinical Research Article
Document Type
Academic Journal
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.
Source
Journal of Clinical Endocrinology & Metabolism. September 2022, Vol. 107 Issue S1, pe3689, 6 p.
Subject
Language
English
ISSN
0021-972X
Abstract
A genetic diagnosis for obesity can be established in an estimated 2% to 9% of patients with severe obesity (1, 2). Since the first report in 1998, variants of the [...]
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 [alpha]-melanocortin-stimulating hormone ([alpha]-MSH) and desacetyl-[alpha]-melanocortin-stimulating hormone (d-[alpha]-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 [alpha]-MSH and d-[alpha]-MSH is also required in humans for feeding control. Key Words: pro-opiomelanocortin, genetic obesity, adrenocorticotropic hormone, melanocortin receptor
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 [alpha]-melanocortin-stimulating hormone ([alpha]-MSH) and desacetyl-[alpha]-melanocortin-stimulating hormone (d-[alpha]-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 [alpha]-MSH and d-[alpha]-MSH is also required in humans for feeding control. Key Words: pro-opiomelanocortin, genetic obesity, adrenocorticotropic hormone, melanocortin receptor