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

Ana Carolina Bueno, Kai Sun, Clarissa Silva Martins, Jorge Elias, Wallace Miranda, Caroline Tao, Maria Cristina Foss-Freitas, Marco Antonio Barbieri, Heloísa Bettiol, Margaret De Castro, Philipp E. Scherer, Sonir R. Antonini

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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 < .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.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number4
DOIs
StatePublished - 2014

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Adiponectin
Obesity
Molecular Weight
Molecular weight
Mutation
Adipose Tissue
Oligomerization
Tissue
Medical problems
Type 2 Diabetes Mellitus
Insulin Resistance
Insulin
Phenotype
Glycosylated Hemoglobin A
Fatty Liver
Dyslipidemias
Age of Onset
Liver
Gestational Age
Young Adult

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

A novel ADIPOQ mutation (p.M40K) impairs assembly of high-molecular-weight adiponectin and is associated with early-onset obesity and metabolic syndrome. / Bueno, Ana Carolina; Sun, Kai; Martins, Clarissa Silva; Elias, Jorge; Miranda, Wallace; Tao, Caroline; Foss-Freitas, Maria Cristina; Barbieri, Marco Antonio; Bettiol, Heloísa; De Castro, Margaret; Scherer, Philipp E.; Antonini, Sonir R.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 4, 2014.

Research output: Contribution to journalArticle

Bueno, Ana Carolina ; Sun, Kai ; Martins, Clarissa Silva ; Elias, Jorge ; Miranda, Wallace ; Tao, Caroline ; Foss-Freitas, Maria Cristina ; Barbieri, Marco Antonio ; Bettiol, Heloísa ; De Castro, Margaret ; Scherer, Philipp E. ; Antonini, Sonir R. / A novel ADIPOQ mutation (p.M40K) impairs assembly of high-molecular-weight adiponectin and is associated with early-onset obesity and metabolic syndrome. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 4.
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title = "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 < .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.",
author = "Bueno, {Ana Carolina} and Kai Sun and Martins, {Clarissa Silva} and Jorge Elias and Wallace Miranda and Caroline Tao and Foss-Freitas, {Maria Cristina} and Barbieri, {Marco Antonio} and Helo{\'i}sa Bettiol and {De Castro}, Margaret and Scherer, {Philipp E.} and Antonini, {Sonir R.}",
year = "2014",
doi = "10.1210/jc.2013-3009",
language = "English (US)",
volume = "99",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
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T1 - A novel ADIPOQ mutation (p.M40K) impairs assembly of high-molecular-weight adiponectin and is associated with early-onset obesity and metabolic syndrome

AU - Bueno, Ana Carolina

AU - Sun, Kai

AU - Martins, Clarissa Silva

AU - Elias, Jorge

AU - Miranda, Wallace

AU - Tao, Caroline

AU - Foss-Freitas, Maria Cristina

AU - Barbieri, Marco Antonio

AU - Bettiol, Heloísa

AU - De Castro, Margaret

AU - Scherer, Philipp E.

AU - Antonini, Sonir R.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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