학술논문
Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant
Document Type
Academic Journal
Author
Valk, Eline S. van der; Kleinendorst, Lotte; Delhanty, Patric J.D.; Voorn, Bibian van der; Visser, Jenny A.; M.Haelst, M. van; Graaff, Laura C.G. de; Huisman, Martin; White, Anne; Ito, Shosuke; Wakamatsu, Kazumasa; Rijke, Yolanda B. de; Akker, Erica L.T. van den; Iyer, Anand M.; Rossum, Elisabeth F.C. van
Source
Journal of Clinical Endocrinology & Metabolism. September 2022, Vol. 107 Issue 9, pe3699, 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-a-MSH is also required in humans for feeding control. Key Words: pro-opiomelanocortin, genetic obesity, adrenocorticotropic hormone, melanocortin receptor Abbreviations: a-MSH, a-melanocortin--stimulating hormone; ACTH, adrenocorticotropin; cAMP, cyclic adenosine 5'-monophosphate; d-a-MSH, desacetyl-[alpha]-melanocortin--stimulating hormone; E[C.sub.50], half-maximal effective concentration; GH, growth hormone; MC1R, melanocortin 1 receptor; MC2R, melanocortin 2 receptor; MC4R, melanocortin 4 receptor; MRAP, melanocortin-2 receptor accessory protein; PC2, prohormone convertase 2; POMC, pro-opiomelanocortin; WT, wild-type.
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-a-MSH is also required in humans for feeding control. Key Words: pro-opiomelanocortin, genetic obesity, adrenocorticotropic hormone, melanocortin receptor Abbreviations: a-MSH, a-melanocortin--stimulating hormone; ACTH, adrenocorticotropin; cAMP, cyclic adenosine 5'-monophosphate; d-a-MSH, desacetyl-[alpha]-melanocortin--stimulating hormone; E[C.sub.50], half-maximal effective concentration; GH, growth hormone; MC1R, melanocortin 1 receptor; MC2R, melanocortin 2 receptor; MC4R, melanocortin 4 receptor; MRAP, melanocortin-2 receptor accessory protein; PC2, prohormone convertase 2; POMC, pro-opiomelanocortin; WT, wild-type.