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

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Pro-opiomelanocortin (POMC) defects are associated with early-onset obesity, hyperphagia, hypopigmentation, and ACTH deficiency.
• Rodent studies indicate that proper cleavage of ACTH to α-MSH and d-α-MSH by PC2 is crucial for regulating food intake and energy balance.

Purpose of the Study:

• To investigate a novel POMC gene variant in two sisters presenting with symptoms suggestive of POMC deficiency.
• To perform functional studies on the identified POMC variant and its impact on ACTH processing and function.

Main Methods:

• Genetic sequencing to identify POMC gene variants.
• Functional assays to assess ACTH cleavage and melanocortin receptor 2 (MC2R) stimulation.
• Clinical evaluation of patients, including hormonal levels and physical characteristics.

Main Results:

• The patients exhibited obesity, hyperphagia, and hypocortisolism, with elevated ACTH levels but normal pigmentation.
• The novel POMC variant resulted in an ACTH defect at the prohormone convertase 2 (PC2) cleavage site.
• The patients' ACTH showed reduced potency in stimulating the MC2R, explaining their hypocortisolism.

Conclusions:

• The findings in these sisters support the hypothesis that adequate cleavage of ACTH to α-MSH and d-α-MSH is essential for human feeding control.
• This study underscores the role of POMC processing in regulating energy balance and highlights a novel genetic cause of obesity and hypocortisolism.