Genetics of adiponectin

doi:10.1016/j.biochi.2012.03.004

Biochimie

Volume 94, Issue 10, October 2012, Pages 2157-2163

https://doi.org/10.1016/j.biochi.2012.03.004 Get rights and content

Abstract

Anti-inflammatory, anti-atherogenic and anti-diabetic properties of adiponectin make this adipokine an attractive target in the metabolism research. Given its biological role, genetic variation in adiponectin affecting its function might consequently play a role in the pathophysiology of various metabolic disorders. In this light, genetic aspects of adiponectin including its gene structure, heritability of serum concentrations and the role of genetic variation have been addressed in multiple genetic studies. Here, we provide a brief summary of adiponectin genetics with focus on gene structure and genetic variation controlling circulating adiponectin levels. We summarize the main findings from genome-wide linkage and association studies that have revealed the major genetic determinants of serum adiponectin. Beside genetic variants in the adiponectin gene, several other genes/loci (ARL15, CDH13, KNG1, FER, ETV5) contributing to the variability in circulating adiponectin have been identified. The majority of these variants are significantly associated with metabolic phenotypes relevant to metabolic diseases (e.g. obesity or type 2 diabetes (T2D)). Considering the protective properties of adiponectin in diseases such as T2D, comprehensive analyses of genetic variants including rare as well as frequent polymorphisms might provide insights on the specific role of adiponectin in the pathophysiology of metabolic diseases.

Highlights

► Strong evidence for the role of genetic variants in the variability of circulating adiponectin. ► Major genetic determinants of adiponectin have been identified but their functional relevance has yet to be determined. ► Additional factors (e.g. environment) which influence mechanisms regulating adiponectin have to be dissected.

Introduction

Energy homeostasis is complexly regulated and its imbalance may result in obesity. Obesity is one of the major factors contributing to the metabolic syndrome, which is defined as a cluster of metabolic abnormalities also including insulin resistance (IR) with type 2 diabetes (T2D), cardiovascular disease (CVD), dyslipidemia and hypertension [1], [2], [3], [4]. In obesity the adipose tissue is expanded and its function changed. For a long time white adipose tissue was thought to act simply as a source of lipid storage. However, the once adopted function of the adipose tissue as a simple passive reservoir for energy storage was extended in the 1990s when it attracted attention as a highly endocrine organ secreting adipocytokines [5] like leptin, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and adiponectin. After the first description of adiponectin in 1995/1996, it became one of the most intensively studied adipokines. Anti-inflammatory [6], anti-atherogenic [7], [8] and anti-diabetic [9], [10] properties as well as a central action modulating the food intake and energy expenditure have been described for adiponectin [11].

Since adipokines regulate a number of critical metabolic pathways, genetic variation that affects their function and efficiency may consequently contribute to various pathophysiologic states. Indeed, there is evidence that genetic variation in adipokine genes could modulate the circulating adipokine levels, which, in turn would be reflected in a specific metabolic alteration (e.g. IR etc.) [12], [13]. Therefore, comprehensive analyses of genetic variants including rare as well as frequent polymorphisms such as single nucleotide polymorphisms (SNPs) might provide insights on the specific role of the studied adipokine in the pathophysiology of metabolic diseases. Here, we provide a brief summary of the genetics of adiponectin as an adipokine attracting attention of the researchers for its protective properties in complex diseases such as obesity, T2D or with coronary heart disease (CHD) [14], [15].

Section snippets

Discovery of adiponectin

Adiponectin was independently discovered by 4 research groups. While Maeda et al. [16] isolated the cDNA of apM1 (adipose most abundant gene transcript 1) from human adipose tissue by large-scale random sequencing, the group around Scherer [17] described a novel 30 kDa secretory protein, initially designated as adipocyte complement-related protein of 30 kDa (ACRP30) which was produced exclusively in adipocytes and showed an over 100-fold increased mRNA during the adipocyte differentiation. In

Gene/protein structure

The adipoQ gene is located on chromosome 3q27, consists of 3 exons, is 15.8 kb long, and codes a 244 amino acid protein with a molecular weight of approximately 26 kDa (according to the ensemble database – http://www.ensembl.org/index.html; ENSG00000181092). Three isoforms have been identified so far. The promoter region of the adiponectin gene includes up-strand sequences, 5′-untranslated region (5′UTR) and important sequence motifs in intron 1. Carrying at least two of them, the sterol

Genetic variation in adiponectin

According to the HapMap database (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap27_B36) there are more than 100 SNPs which map within the adiponectin locus and form 2 major haplotype blocks. These polymorphisms including rare variants with minor allele frequency (MAF) <5% are represented by 21 tagging SNPs (linkage disequilibrium blocks with r² > 0.8). Based on the NCBI database (http://www.ncbi.nlm.nih.gov/SNP/snp_ref. cgi?locusId=9370), 29 SNPs are located in the coding region whereat

Genetic variants and clinical associations

Adiponectin is strongly involved in the regulation of insulin sensitivity and glucose homeostasis. Therefore, it is not surprising that a decrease of plasma adiponectin associates with deterioration of virtually all parameters of the metabolic syndrome, including T2D and CVD [36], [37], [38], [39]. Also transgenic and adiponectin deficient mice models support the functional role of adiponectin on various components of the metabolic syndrome and T2D [38], [40], [41]. In line with this, genetic

Functional consequences of genetic variants

Although there is strong evidence for several polymorphisms being responsible for variation in plasma adiponectin, the precise mechanisms underlying associations of these genetic variants in adiponectin with circulating adiponectin levels and metabolic traits remains unclear and has yet to be determined. However, as mentioned above, there are multiple physiologically important binding sites, including Sp1, SREBP, AP1 and C/EBP binding sites [27], [28], [29], [30], [31], [32], [33], [34], [42]

Linkage studies

Estimated 50–60% of variation in normal circulating adiponectin levels can be explained by genetic variation [39], [63], [64], [65], [66], [67]. It is likely that besides genetic variants within the adiponectin gene, further polymorphisms have to contribute to the variability in serum adiponectin concentrations. Hypothesis free genome-wide approaches provide a valuable tool to accomplish this mission. In fact, several linkage and genome-wide association studies (GWAS) for adiponectin have been

Conclusion

In conclusion, there is strong evidence for the role of genetic variants in the variability of circulating adiponectin. Although the major genetic determinants of adiponectin have been identified, their functional relevance has yet to be determined to clearly characterize mechanisms regulating adiponectin as well as the influence of modifying factors such as environment.

Acknowledgements

This work was supported by grants from the Federal Ministry of Education and Research (BMBF), Integrated Research and Treatment Center IFB Adiposity Diseases K7-37, Deutsche Forschungsgemeinschaft (DFG; project KO 3880/1-1 to PK), DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland; to MS, PK).

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Atrial fibrillation (AF) is a common heart disease associated with cardiac dysfunction. Adiponectin is an abundant protein produced by adipocytes that regulates metabolism and inflammation in the body. Studies have reported a link between AF and circulatory adipokines. The objective of the study is to investigate the associations between adiponectin serum level and the ADIPOQ rs1501299 (276G/T) SNP with AF.
The study included a total of 112 AF cases and 112 matched healthy controls. Serum adiponectin was analyzed using an ELISA assay. Genotyping of rs1501299 was performed using PCR-RFLP technique.
The results showed that the level of adiponectin in the serum was significantly higher (P < 0.01) in AF group versus the controls. When the sample was stratified by sex, the magnitude of increases in adiponectin levels among female AF patients (87.6%) was higher than that of male patients (33.2%). Multivariate regression model showed that gender was related to adiponectin levels among the patient group (P < 0.001). In sex-specific multivariate regression, adiponectin was associated with BMI in female patients (P < 0.05) and with glucose blood level among male patients (P < 0.05). Finally, the study showed no association between ADIPOQ rs1501299 SNP and AF (P > 0.05).
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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
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Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10⁻⁷). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r² > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10⁻⁴) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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Citation Excerpt :
However, sometimes such polymorphisms, has no impact on the adiponectin concentration, but still associated with the metabolic diseases (Asma and Mohd, 2015). There are 683 single nucleotide polymorphisms (SNPs) mapped within the adiponectin locus in human (www.ncbi.nlm.nih.gov), 33 of these SNPs were cited in the PubMed (Breitfeld et al., 2012). Several studies have shown associations of ADIPOQ polymorphisms with diabetes mellitus, obesity and cardiovascular diseases (Han et al., 2011).
Type 2 diabetes mellitus (T2DM) incidence is increasing globally and nationally. The etiology of the disease includes environmental and genetic factors. Polymorphism of adiponectin gene was found to be implicated in the pathogenesis of T2DM in numerous populations.
A case-control study was conducted to assess the association of rs2241766 and rs822395 SNPs of adiponectin gene (ADIPOQ) with T2DM in Iraqi population. The study included 400 patients with T2DM and 400 healthy individuals served as a control group. Serum lipid concentrations, insulin level and the index of insulin resistance (HOMA) were measured. The genotyping of ADIPOQ for rs2241766 and rs822395 SNPs was performed by PCR-RFLP.
The genotype distribution of rs2241766 SNP indicated a significant increase of carriers of the homozygous GG (OR: 5.04, CI95%: 2.27–11.19, P: 0.0001) and heterozygous TG (OR: 1.7, CI95%: 1.22–2.39, P: 0.002) variants when compared with those of the wild type, suggesting a risk factor of 2 and 5 to develop the disease. The minor allele frequency (MAF) G was observed to be significantly (P: 0.0001) higher in patients (22%) when compared with the control group (11.74%). Results of rs822395 SNP failed to exhibit a significant difference. Changes of BMI, cholesterol, triglycerides, insulin and insulin resistance index values in the diabetic patients seemed to be parallel with the presence of MAF of rs2241766 SNP.
The rs2241766T>G SNP of adiponectin gene is a risk factor for the development of T2DM in Iraqi population and directs the changes of serum lipid concentrations as well as insulin resistance.
The effects of anthocyanins on body weight and expression of adipocyte's hormones: Leptin and adiponectin
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Reducing or stabilising leptin levels could result in reduction of obesity induced inflammation in general. Specifically and highly secreted by adipocytes, adiponectin (ApN) is one of the most important adipokines, a modulator of food intake and energy expenditure (Breitfeld, Stumvoll, & Kovacs, 2012; Guerre-Millo, 2008). In addition to this, adiponectin has an array of anti-inflammatory, anti-atherogenic, anti-diabetic and anti-obesity properties making it one of most intensively studied adipokines (Lee et al., 2009; Ouchi et al., 1999, 2000; Yokota et al., 2000).
The purpose of the study was to assess the effects of anthocyanin-rich Queen Garnet plum juice (QGPJ) on body weight and expression of leptin and adiponectin. Queen Garnet plum is a Japanese plum (Prunus salicina) cultivar developed through a Queensland Government breeding program with very high levels of anthocyanins (272 mg/100 g). Twenty healthy volunteers were supplemented with 200 ml/day of QGPJ and placebo drink for 4 weeks. Supplementation with QGPJ significantly reduces body weight and BMI (p < 0.05) with the average decrease of 0.6 kg in body weight and 0.2 units in BMI over the period of 4 weeks. Furthermore, consumption of QGPJ significantly increases adiponectin blood levels (p < 0.05) (average increase of 3.83 µg/mL) and decreases leptin blood levels (average decrease of 1.31 ng/mL). QGPJ may have potential to be used as a functional food for preventing obesity and obesity related disorders.
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Adipose tissue functions as a dynamic endocrine organ secreting multiple proteins, factors, and hormones into the systemic circulation that are collectively described as adipokines. Adipokines exert pleiotropic effects on target tissues/organs thereby regulating energy homeostasis, metabolism, and insulin sensitivity, as well as immune and cardiovascular functions. Expanding adipose tissue in obesity undergoes a change in the adipokine secretion profile characterized by an increase of proinflammatory adipokines and suppression of anti-inflammatory adipokines increasing proinflammatory pathways within adipose tissue depots and creating an adverse circulating adipokine profile, resulting in a chronic, low-grade, systemic inflammatory state. Compelling evidence directly links the adverse proinflammatory adipokine profile in obesity with a spectrum of detrimental cardio-metabolic effects including hepatic, skeletal muscle, and myocardial insulin resistance, hypertension, atherosclerosis, hypercoagulability, thrombosis, and endothelial and cardiac dysfunction. This chapter presents a brief overview of the nature of adipose tissue in obesity and focuses on selected adipokines that have direct and indirect effects on the heart and cardiovascular system.
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Diabetes incidence is increasing worldwide. Many studies demonstrated that polymorphisms within the adiponectin gene could be associated with type 2 diabetes mellitus (T2DM).
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Adiponectin gene polymorphism rs266729 is involved in the pathogenesis of T2DM. In addition this SNP may play a role in the development of cardiovascular diseases and metabolic syndrome by affecting HDL and insulin levels.

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Research paperGenetics of adiponectin

Abstract

Highlights

Introduction

Section snippets

Discovery of adiponectin

Gene/protein structure

Genetic variation in adiponectin

Genetic variants and clinical associations

Functional consequences of genetic variants

Linkage studies

Conclusion

Acknowledgements

Prim. Care

Blood

Gend. Med.

Cell Metab.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell Endocrinol.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gene

J. Am. Coll. Cardiol.

Diabetes Res. Clin. Pract.

Metabolism

Atherosclerosis

Am. J. Hum. Genet.

Am. J. Hum. Genet.

J. Biol. Chem.

Global and societal implications of the diabetes epidemic

Nature

Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults

New Engl. J. Med.

Clustering of metabolic abnormalities in obese individuals: the role of genetic factors

Ann. Med.

Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ

Proc. Nutr. Soc.

Novel modulator for endothelial adhesion molecules – adipocyte-derived plasma protein adiponectin

Circulation

Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappa B signaling through a cAMP-dependent pathway

Circulation

The relationship between adipokines, metabolic parameters and insulin resistance in patients with metabolic syndrome and type 2 diabetes

J. Int. Med. Res.

Increased plasma levels of adipokines in preeclampsia: relationship to placenta and adipose tissue gene expression

Am. J. Physiol-Endoc.

Plasma adipokine and inflammatory marker concentrations are altered in obese, as opposed to non-obese, type 2 diabetes patients

Eur. J. Appl. Physiol.

Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients

Arterioscl. Throm. Vas.

The role of the novel adipocyte-derived hormone adiponectin in human disease

Eur. J. Endocrinol.

Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma

J. Biochem.

Signalling role of adipose tissue: adipokines and inflammation in obesity

Biochem. Soc. Trans.

Adipose tissue dysfunction in obesity, diabetes, and vascular diseases

Eur. Heart J.

Adiponectin: a key player in obesity related disorders

Curr. Pharm. Des.

Adiponectin genetic variability, plasma adiponectin, and cardiovascular risk in patients with type 2 diabetes

Diabetes

Biomarkers of adiponectin: plasma protein variation and genomic DNA polymorphisms

Biomarker Insights

Variations in adipokine genes AdipoQ, Lep, and LepR are associated with risk for obesity-related metabolic disease: the modulatory role of gene-nutrient interactions

J. Obes.

Regulation of gelatin-binding protein 28 (GBP28) gene expression by C/EBP

Biol. Pharm. Bull.

Research paper
Genetics of adiponectin