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

Abstract

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.

Proopiomelanocortin (POMC) and psychodermatology

“…14 The patients had obesity, hyperphagia and hypoadrenalism, with markedly elevated levels of ACTH, but unaffected pigmentation. 14 Functional studies of this variant imply that their ACTH has decreased effectiveness at stimulating the melanocortin MC2R, leading to low levels of circulating F I G U R E 2 Gene structure and post-translational processing of POMC. POMC in mammals consists of three exons, of which exons 2 and 3 are translated.…”

“…cortisol. 14 The hyperphagia and obesity provide evidence that adequate cleavage of ACTH to α-MSH and desacetyl-α-MSH is also required in humans for feeding control, but may not be necessary for melanogenesis. 14 A novel MC4R agonist, setmelanotide, has shown promising results with regard to weight loss in patients with POMC deficiency.…”

“…[65][66][67] The exact purpose of POMC-derived peptides in immunomodulation is still a large field requiring much further study. 1,2,4,6,7,10,11,[13][14][15][16][17][18]28,67,68 The HF has an unusual immune system. 67,68 The proximal epithelium of an anagen HF is an area of 'immune privilege', characterized primarily by a very low level of expression of major histocompatibility (MHC) class antigens.…”

“…4,10,[78][79][80] 1.11 | Skin pigmentation in general, the HPA axis and psychodermatology POMC, via ACTH and α-MSH, are amongst the principle neuroendocrine factors affecting skin pigmentation, through actions on the MC1-R in melanocytes. 4,10,11,[13][14][15][16][17][18][20][21][22]28,29,31,80 For millennia, Europeans have discriminated against those with darker skins, often Africans. 81 This was sometimes institutionalized in the form of very flawed academic study of human pigmentation.…”

“…84 Polymorphisms associated with loss of function of MC1R are associated with an increased risk of photoageing, freckles, red-hair and all types of common skin cancers, independent of these behavioural variables. 4,10,11,[13][14][15][16][17][18][20][21][22]28,29,31,80,81,85,86 The reinforcing effects of frequent tanning may be explained by the role of endorphins in the physiologic response to the UV exposure of sunbeds. 87,88 In a randomized controlled trial, frequent sunbed users demonstrated a preference for UV-emitting sunbeds over non-UV-emitting sunbeds in a blinded trial.…”