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

Autor(es):Mostrar menos -

Bueno, Ana Carolina ^[1] ; Sun, Kai ^[2] ; Martins, Clarissa Silva ^[3] ; Elias Junior, Jorge ^[3] ; Miranda, Wallace ^[3] ; Tao, Caroline ^[2] ; Foss-Freitas, Maria Cristina ^[3] ; Barbieri, Marco Antonio ^[1] ; Bettiol, Heloisa ^[1] ; de Castro, Margaret ^[3] ; Scherer, Philipp E. ^[2] ; Antonini, Sonir R. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pediat, BR-14049900 Sao Paulo - Brazil

^[2] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Touchstone Diabet Ctr, Dallas, TX 75390 - USA

^[3] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Internal Med, BR-14049900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 99, n. 4, p. E683-E693, APR 2014.
• Citações Web of Science: 11

Resumo

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 mu g/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 mu g/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 mu g/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. (AU)

• Processo FAPESP: 09/17095-9 - Interação entre polimorfismos no gene da adiponectina e o consumo habitual de gorduras, carboidratos e fibras e sua influência sobre o perfil cárdio-metabólico de adultos jovens de acordo com o tamanho ao nascer.
• Beneficiário: Ana Carolina Bueno de Queiroz Arruda
• Modalidade de apoio: Bolsas no Brasil - Doutorado