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

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 < .05) and family noncarriers (9.4% ± 1% vs 42% ± 0.5%; P = .05). Both mRNA and protein levels of adiponectin were increased in the AT of the proband (2.3- and 1.6-fold, respectively). However, the high-molecular weight to total adiponectin ratio of adiponectin was decreased (3.3-fold). Moreover, the expressions of ADIPOR1 and ADIPOR2 were significantly down regulated in the AT of the proband (6- and 1.2-fold, respectively). The results were confirmed by in vitro studies on the recombinant murine homologous mutation (p.M43K). The proband's cardiometabolic phenotype progression was further characterized: born small for gestational age and adolescence-onset obesity; insulin resistance (homeostasis assessment model of insulin resistance of 4.7), and dyslipidemia at 25 years; decreased high-molecular weight adiponectin (0.24 μg/mL- 10%), hypertension (180/120 mm Hg), steatosis (fat liver = 40% ± 6%), increased carotid intimamedia thickness at 31 years, and type 2 diabetes (glycosylated hemoglobin = 6.6%) at 34 years of age. Of note, all of the affected family members presented features of metabolic syndrome. Conclusion: The newly identified ADIPOQ p.M40K mutation associates with severe cardiometabolic dysfunction due to the impairment of high-molecular weight adiponectin complex formation.