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

• Published in: The journal of clinical endocrinology and metabolism Vol. 99; no. 4; pp. E683 - E693
• Main Authors: Bueno, Ana Carolina, Sun, Kai, Martins, Clarissa Silva, Elias Junior, Jorge, Miranda, Wallace, Tao, Caroline, Foss-Freitas, Maria Cristina, Barbieri, Marco Antonio, Bettiol, Heloísa, de Castro, Margaret, Scherer, Philipp E., Antonini, Sonir R.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.04.2014; Copyright by The Endocrine Society
• Subjects: Adiponectin; Adiponectin - chemistry; Adiponectin - genetics; Adiponectin - metabolism; Adipose tissue; Adult; Age; Age of Onset; Amino Acid Substitution; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - genetics; Cardiovascular Diseases - metabolism; Case-Control Studies; Diabetes; Diabetes mellitus (non-insulin dependent); Dyslipidemia; Fatty liver; Female; Gestational age; Hemoglobin; Homeostasis; Humans; Insulin resistance; Lysine - genetics; Male; Metabolic syndrome; Metabolic Syndrome - epidemiology; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Methionine - genetics; Middle Aged; Molecular Weight; mRNA; Mutation; Mutation, Missense; Obesity; Obesity - epidemiology; Obesity - genetics; Obesity - metabolism; Oligomerization; Phenotypes; Protein folding; Protein Multimerization - genetics; Small for gestational age; Steatosis; Young Adult; Young adults
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2013-3009

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 (2.4 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.Conclusion:The newly identified ADIPOQ p.M40K mutation associates with severe cardiometabolic dysfunction due to the impairment of high-molecular weight adiponectin complex formation.