A NovelADIPOQMutation (p.M40K) Impairs Assembly of High-Molecular-Weight Adiponectin and Is Associated With Early-Onset Obesity and Metabolic Syndrome

Abstract

The phenotypic effects of ADIPOQ mutations early in life, prior to type 2 diabetes onset, have not been studied. The objective of the study was to characterize the impact of a novel ADIPOQ mutation in vitro and in vivo. The design of the study was ADIPOQ screening, adiponectin oligomerization, and cardiometabolic phenotype assessment. Fourteen hypoadiponectinemic (<3 μg/mL) and 686 normoadiponectinemic young adults (23-25 y) were prospectively followed up since birth. Human and recombinant murine mutant adiponectin oligomerization, the proband's ADIPOQ and ADIPOR1/R2 adipose tissue (AT) expression, and cardiometabolic profile were measured. The heterozygous ADIPOQ p.M40K mutation was identified in one hypoadiponectinemic male (2.4 μg/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 intima-media 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. The newly identified ADIPOQ p.M40K mutation associates with severe cardiometabolic dysfunction due to the impairment of high-molecular weight adiponectin complex formation.