A novel ADIPOQ mutation (p.M40K) impairs assembly of high-molecular-weight adiponectin and is associated with early-onset obesity and metabolic syndrome

Abstract

Context: The phenotypic effects of ADIPOQ mutations early in life, prior to type 2 diabetes onset, have not been studied. Aim: The objective of the study was to characterize the impact of a novel ADIPOQ mutation in vitro and in vivo. Design: The design of the study was ADIPOQ screening, adiponectin oligomerization, and cardiometabolic phenotype assessment. Subjects: Fourteen hypoadiponectinemic (<3 μg/mL) and 686 normoadiponectinemic young adults (23-25 y) were prospectively followed up since birth. Main Outcome Measures: Human and recombinant murine mutant adiponectin oligomerization, the proband's ADIPOQ and ADIPOR1/R2 adipose tissue (AT) expression, and cardiometabolic profile were measured. Results: The heterozygous ADIPOQ p.M40K mutation was identified in one hypoadiponectinemic male (2.4μg/mL) and three other family members. Carriers presented a marked reduction of serum high-molecular weight to total adiponectin ratio when compared with controls (9.4% ± 1% vs 56.6% ± 13%; P