ADIPOQ, Obesity and Type 2 Diabetes

ADIPOQ is also known as Acrp30 (adipocyte complement–related protein 30), GBP28 (gelatin-binding protein 28), ACDC (adipocyte collagen–domain containing) and AMP1 (adipose most abundant transcript 1). Its protein product adiponectin is a 30 kDa protein (244 amino acids) consists of an N-terminus signal peptide, a collagen-like domain in the middle and a globular domain at the C-terminus.  After synthesis in the adipocytes, adiponectin molecules form multimeric complexes through disulfide bounds in the collagen-like domain. The multimeric complexes are secreted to the blood circulation in mainly three isoforms: the basic low-molecular-weight trimer isoform; the medium-molecular-weight hexametric isoform; and the high-molecular-weight multimer (up to 18 mers) isoform.  The high-molecular-weight isoform adiponectin is believed to be the biologically active form that activates the downstream events in both skeletal muscle and the liver (Kadowaki and Yamauchi, 2005). Several rare ADIPOQ gene mutations affecting the multimerization and consequently the biological function of the protein have been characterized. For example, the Arg112Cys and Ile164Thr mutants do not assemble into trimers, leading to the clinic symptom hypoadiponectinemia. The Gly84Arg and Gly90Ser mutants are able to assemble into trimers and hexamers but are unable to form the high-molecular-weight multimers, leading directly to diabetes.

Adiponectin activates down-stream events through cell surface receptors.  In skeletal muscle, low-molecular-weight as well as high-molecular-weight adiponectin up-regulates PPARα and activates AMPK (AMP kinase) through the AdipoR1 receptors.  Up-regulation of PPARα and its target genes such as CD36, ACC (acyl-coenzyme A oxidase), and uncoupling protein 2 leads to increased fatty acids β-oxidation.  Activation of AMPK leads to increased glucose transport 4 translocation and increased glucose uptake. In the liver, only the high-molecular-weight adiponectin can act through the AdipoR2 receptor, leading to the up-regulation of PPARα and the activation of AMPK.  The increased PPARα increases β-oxidation, as it does in the skeletal muscle. However, the activation of AMPK inhibits the activities of genes that are involved in gluconeogenesis.  Therefore, the overall functions of adiponectin are increased fat burning and decreased glucose in blood circulation, and consequently decreased fatty acids content and improved insulin sensitivity (Fig. 3).

Figure 3. Mechanisms of adiponectin on fat burning (β-oxidation) and insulin sensitivity improvement in the liver and skeletal muscle. WAT, White adipose tissue; PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; TG, triglycerides; ACC, acyl-coenzyme A oxidase; AMP, Adenosine monophosphate; AMPK, AMP kinase (Adopted from Kodowaki & Yamauchi, 2005).

The expression of ADIPOQ is regulated by several transcription factors including PPARγ (peroxisome proliferation–activated receptor-γ), liver receptor homolog-1, CCAAT/enhancer-binding protein (C/EBP), nuclear factor-Y and sterol-regulatory element–binding protein-1c (Warodomwichit et al, 2009). Factors determining serum adiponectin level includes genetic background, ethnicity, body weight, sex, age, and health status.  Dietary and medicinal practice also regulates the level of adiponectin in blood circulation. For example, adiponectin concentration is normally higher in White Europeans than in Southern Asians and Africans, higher in females than males due to the inhibitory effect of testosterone on adiponectin production, decreases with aging due to sex hormone changes. PPARγ agonists such as TZD enhance the expression of adiponectin mRNA in adipose tissue and increase serum adiponectin concentrations in both human subjects and rodents. Dietary fat composition as well as percentage of fat as total energy intake regulates the adiponectin concentrations through the various transcription factors mentioned above (Fig.1).

Adiponectin-deficient mice exhibited characteristics of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, and hypertension. Transgenic mice over-expressing adiponectin by 3-fold in circulation raised lipid clearance and lipoprotein lipase activity, and improved insulin-mediated suppression of endogenous glucose production, thereby improving insulin sensitivity (Combs et al, 2004).

ADIPOQ gene polymorphisms

The ADIPOQ gene includes three exons, spanning a total of 16 kb of genomic sequence. There are about 390 identified SNPs in the ADIPOQ gene.  More than a dozen of the ADIPOQ SNPs have been associated with insulin resistance and/or obesity traits in some but not all studies. These SNPs are distributed in a two linkage disequilibrium blocks that are represented by the promoter region haplotypes determined by the two SNPS rs17300539 (−11391G>A) and rs266729 (−11377C>G) and the gene region haplotypes determined by the other two SNPs rs2241766 (+45T>G) in exon 2 and rs1501299 (276G>T) in intron 2 (Menzaghi et al, 2007).

For the two SNPs that determining the promoter region haplotypes, the minor allele of −11391G>A is associated with increased serum adiponectin concentrations due to its increases transcriptional activity (Bouatia-Naji et al, 2006) and the minor allele of −11377C>G is associated with decreased adiponectin level, presumably also due to its effect on ADIPOQ gene expression.  The minor allele of –11391G>A is common in Caucasians (7-10%) and rare in other ethnic groups (<5%) while the minor allele of −11377C>G is quite common in all ethnic groups with a frequency of 27% in general population (Table 2).

Table 2. The allele distributions of ADIPOQ -11391G>A and -11377C>G SNPs

Ethnic groups	-11391G>A		-11377C>G
	Major allele G	Minor allele A	Major allele C	Minor allele G
Africans	95-99%	1-5%	72-82%	18-28%
Asians	97-100%	*0-3%	74-77%	23-26%
Caucasians	90-93%	7-10%	73-75%	25-27%
Hispanics	96%	4%	68%	32%

*The -11391G>A polymorphism was about 3% in Japanese and was not detected in Korean and Chinese population in the studies published.

Linkage disequilibrium analyses of the common SNPs in ADIPOQ gene suggest these two SNPs are in the same closely linked haplotype block, although the linkage between them are low in some studies and high in others (Hivert et al, 2008; Warodomwichit et al, 2009; Wessal et al, 2011). Never the less, studies in Caucasians demonstrate that a G-G haplotype (major allele of -11391G>A and minor allele of -11377C>G), which has a frequency of about 25% in Caucasians, about 15% in Africans and 23-26% in Asians (Table 3), is the promoter region risk haplotype associated with low-circulating adiponectin concentrations and increased risk for T2DM (Vasseur et al, 2002; Vasseur et al, 2005).

Table 3. The distribution of the promoter region haplotypes and their effects on adiponectin concentration.

Haplotype	Frequency			Adiponectin concentration
	Caucasians	Africans	Asians
G-C	68%	82%	74-77%	Baseline
G-G	25%	15%	23-26%	20% decrease
A-C	7%	3%	0	10% increase

Since the A-G haplotype has never been detected, the haplotype genotypes and their effect on adiponectin concentration can be determined by the individual genotype of these two SNPs (Table 4).

Table 4. The promoter region haplotype genotypes and associated adiponectin concentration.

SNP genotypes	Haplotype genotypes	Risk haplotype	Adiponectin concentration
-11391GG/-11377CC	G-C/G-C		Baseline
-11391GG/-11377CG	G-C/G-G	One copy of G-G	20% decrease
-11391GG/-11377GG	G-G/G-G	Two copies of G-G	40% decrease
-11391GA/-11377CC	G-C/A-C		10% increase
-11391GA/-11377CG	G-G/A-C	One copy of G-G	10% decrease
-11391AA/-11377CC	A-C/A-C		20% increase

For the two SNPs that determining the gene region haplotypes, the +45T>G polymorphism is high in Asians and rare in Africans while the +276G>T polymorphism is common in general population (Table 5).  The association of both SNPs with T2DM was first reported in Japanese population (Hara et al, 2002). Subsequent studies revealed that the major alleles of these two SNPs are associated with lower serum adiponectin levels and increased risks for T2DM, and they are in linkage disequilibrium.

Table 5. The allele distributions of ADIPOQ +45T>G and +276G>T SNPs

Ethnic groups	+45T>G		+276G>T SNPs
	Major allele T	Minor allele G	Major allele G	Minor allele T
Africans	96%	4%	79%	21%
Asians	62-82%	18-38%	69-71%	29-31%
Caucasians	80-90%	10-20%	70-74%	26-30%
Hispanics	80%	20%	76%	24%

The haplotype that has major alleles at both SNP sites (45T-276G) is the most common one and the risk haplotype that associates with lower adiponectin concentration (Table 6), higher body weight, increased waist circumference, higher systolic and diastolic blood pressure, higher fasting glucose and insulin levels, higher insulin resistance, and higher total to HDL cholesterol ratio.  The association is dependent on dosage (number of haplotype copies), but is independent of sex, age, and body weight. The two less common haplotypes 45T-276T and 45G-276G are associated with higher serum adiponectin levels in a dose-dependent association. The haplotype that has minor alleles at both sites (45G-276T) are rarely detected (Menzaghi et al, 2002; Sutton et al, 2002; Mackevics et al, 2006; Shin et al, 2006) so the haplotype genotypes can be deduced from the genotype of individual genotypes (Table 7).

Table 6. The distribution of the gene region haplotypes and associated effects on adiponectin concentrations.

Haplotype	Frequency			Adiponectin concentration
	Caucasians	Asians	Hispanics
T-G	50-59%	41%	56%	Baseline
G-G	12-20%	30%	21%	15% increase
T-T	22-29%	29%	23%	11% increase

Table 7. The gene region haplotypes and associated serum adiponectin concentration (Derived from Mackevics et al, 2006).

SNP genotypes	Haplotype genotypes	Adiponectin (μg/ml)	% increase	Note
+45TT/+276GG	T-G/T-G	7.04	0	Two copies of T-G
+45TT/+276GT	T-G/T-T	7.84	11	One copy of T-G
+45TT/+276TT	T-T/T-T	8.54	21
+45TG/+276GG	T-G/G-G	8.07	15	One copy of T-G
+45TG/+276GT	T-T/G-G	8.04	14
+45GG/+276GG	G-G/G-G	10.05	43

Since the +45T>G is a synonymous SNP in the coding region of the gene, meaning the nucleotide change does not change the amino acid in the adiponectin protein, and the +276G>T is in intron region, meaning the variation itself does not affect the expression of the ADIPOQ gene, it is speculated these two SNPs are in a linkage disequilibrium with other SNPs that are critical for ADIPOQ gene expression.  Indeed, in the two populations that have been studied, the T-G haplotype was in almost complete linkage disequilibrium with an A insertion in the 3’-UTR (SNP2019 del/insA), a region plays a pivotal role in the control of ADIPOQ gene expression (Menzaghi et al, 2002).

Disease association

Obesity. As adiponectin is synthesized by the adipocytes, one would expect a positive correlation between adiponectin level and fat mass (thus the body weight).  However, various studies have concluded that serum adiponectin level is negatively correlated with body weight. In general population, the adiponectin levels are higher in lean people and lower in overweight ones. In an individual person, adiponectin level increases with weight loss and decreases with weight gain. No matter if a person lose weight by exercise, by dietary manipulation, by gastric bypass surgery or due to the eating disorder anorexia nervosa, his/her serum adiponectin level would increase. This paradox is explained on one hand by the observation that not all adipocytes express and secretes adiponectin. Most of the serum adiponectin is secreted by subcutaneous adipose tissue distributed in lower extremity and trunk section of the body.  Adiponectin mRNA levels were much lower in visceral adipose tissue. On the other hand, ADIPOQ gene expression is regulated by transcription factors such as PPARγ that are in turn regulated by circulating fatty acids concentration.  In overweight and obese individuals, the circulating fatty acids concentration is higher. Therefore, the expression of ADIPOQ and the serum adiponectin level are lower.  The opposite is true for lean individuals.

In a study of French Caucasians involving 703 morbidly obese subjects (BMI 47.6±7.4 kg/m2), 493 obese subjects (30≤BMI<40 kg/m2) and 808 non-obese subjects (BMI<30 kg/m2), clear relationships between adiponectin and body weight, and between adiponectin and the promoter region genotypes were demonstrated (Table 8).

Table 8. Adiponectin concentration (μg/ml) in relation to the promoter region haplotypes genotypes and body weight (derived from Vasseur et al, 2005).

Haplotype genotype	Non-obese group	Obese-group	Morbidly obese group	Note
G-G/G-G	5.76	5.3	4.01	Two copies of G-G
G-C/G-G	6.06	5.41	4.47	One copy of G-G
G-C/G-C	6.17	5.81	4.91
G-G/A-C	7.3	5.78	5.7	One copy of G-G
G-C/A-C	7.5	7.1	5.46
A-C/A-C	8.32	10.65	7.08

For the gene region haplotypes, the copy number of the risk haplotype T-G correlates negatively with adiponectin level and positively with BMI in both Asian and Caucasians (Table 9). The results for the Asians are from a study involving 363 Korean subjects (Chung et al 2009) and the results for Caucasians are from the SAPHIR (Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk) study involving 1745 subjects (Mackevics et al, 2006).

Table 9. The gene region risk haplotype (T-G) copy number in relation to BMI and adiponectin concentration (Derived from Chuang Chung et al, 2009)

The gene region risk haplotype (T-G)	Asians (Korean Study)		Caucasians (SAPHIR study)
	Adiponectin (μg/ml)	BMI	Adiponectin (μg/ml)	BMI
2 copies	4.4	25.4	7.04	26.9
1 copy	4.72	25.3	7.85	26.7
0 copy	4.99	25.2	8.46	26.7

T2DM. Adiponectin functions as an insulin sensitizer by increasing fat burning and decreasing blood glucose level via increased glucose intake in skeletal muscle and inhibited glucose synthesis in the liver (Fig. 1). The correlation of adiponectin level and insulin sensitivity is so consistent that the serum adiponectin concentration alone can be used as a biomarker for insulin resistance (Trujillo & Scherer, 2005; Turer & Scherer, 2012). Numerous reports have been published on the association of ADIPOQ gene polymorphism and insulin resistance or T2DM. Most of the associations are positive in one population but negative in others (Han et al, 2011).  So far the most consistent associations observed were the T2DM risk haplotypes in the promoter region risk haplotype (G-G) and the gene region risk haplotype (T-G). For example, in case control studies of more than 2000 subjects, the promoter region risk haplotype (G-G) were associated with low adiponectin levels and 20% increased risk for T2DM cases in Caucasian population (Vasseur et al, 2002; Vasseur et al, 2005; Schwarz et al, 2006). The gene region risk haplotype (T-G) has been associated with 5-10% increased T2DM in Caucasian and in Asian populations (Menzaghi et al, 2002; Sutton et al, 2002; Mackevics et al, 2006; Shin et al, 2006).

Cardiovascular diseases. In addition to fat mass control and insulin-sensitizing function, adiponectin has direct anti-atherogenic effects on the arterial wall by inhibiting monocyte adhesion to the endothelium, smooth muscle cell proliferation, and foam cell formation and by improving the body lipid profile. All four polymorphisms involved in the haplotypes here have been associated with increased cardiovascular diseases in certain population.  But the associations are far from conclusive than their associations with T2DM (Menzaghi et al, 2007; Wassel et al, 2010; Wassel et al, 2011; Zhang et al, 2012).

Dietary interactions

Circulating level of adiponectin in a specific individual is pretty consistent, reflecting dietary intake over time. Acute dietary changes are unlikely to have impact on adiponectin level immediately (Pischon et al, 2005). But long term dietary modulations do impact the concentration of adiponectin in serum, consequently the risks for obesity and T2DM. Controlled feeding studies in animal models and dietary interventional studies in human population show that diets rich in saturated fatty acids and excess calorie intake decreases adiponectin level whereas diets rich in unsaturated fatty acids and calorie restriction lead to increased adiponectin (Reis et al, 2010; Silva et al, 2011).  Gene-nutrition interaction studies revealed ADIPOQ gene polymorphism play an important role in response to dietary factors.

In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study involving 1,083 overweight but healthy American Caucasians, carriers of the minor A-allele of the – 11391G>A SNP had significantly lower BMI than the noncarriers when total fat intake is 35% or more of the energy and when the monounsaturated fatty acids (MUFAs) intake was above the median (≥13% of energy intake). However, when total fat intake was less than 35% or when the MUFA intake was less than 13%, no genotype-related differences for BMI or obesity was detected (Table 10). Furthermore, while total fat and MUFA intake is positively correlated with BMI for the wide type (GG) genotypes, they are negatively correlated with BMI for A-allele carriers (Table 10). Since BMI is positively associated with risks for T2DM, it is reasonable to deduct from these results and predict that high fat and high MUFA diets increases the risks for T2DM in GG genotypes and decrease the risks in the minor A-allele carriers. Therefore, low fat diet (<35% total energy) is recommended for GG genotype and high MUFA diet (≥13%) is recommended for A-allele carriers.

Table 10: Dietary fat and ADIPOQ -11391G>A genotype interaction on average BMI (derived from Warodomwichit et al, 2008).

Dietary factors		Genotypes
		GG	GA+AA
Total fat	<35%	28.5	28.5
	≥35%	29	27.5
MUFA	<13%	28.5	28.6
	≥13%	29.1	27.1

Although the GOLDN study did not detect any interaction between the -11377C>G polymorphism and dietary total fat or MUFA content, a controlled study in normal weight population reported that after switching from high SFA (saturated fatty acids) to MUFA-rich diet, - 11377 CC homozygotes were significantly less insulin resistant compared with G-allele carriers (Perez-Martınez et al, 2008). In this study, healthy volunteers (30 men and 29 women) consumed 3 diets for 4 weeks each: an initial period during which all subjects consumed a SFA-rich diet (38% total fat, 20% SFA), followed by a carbohydrate-rich diet (CHO) (30% total fat, 55% carbohydrate) or a monounsaturated fatty acid (MUFA)-rich diet (38% total fat, 22% MUFA) following a randomized, crossover design. After participants consumed each diet, peripheral insulin sensitivity and plasma adiponectin concentrations were measured. The CC homozygous men for the -11377 C>G polymorphism showed a significantly greater decrease in the steady-state plasma glucose concentrations when changing from the SFA-rich (8.95 mmol/L) to the MUFA-rich (6.04 mmol/L) and CHO-rich (6.35 mmol/L) diets than did those carrying the minor G allele (SFA, 6.65 mmol/L; MUFA, 6.45 mmol/L; CHO, 5.83 mmol/L). Interestingly, these gene-dietary interactions were not detected in female participants, presumably due to the overall lower plasma adiponectin concentrations in men than in women. These results suggest that low-fat, high MUFA and/or high carbohydrate diet are beneficial for men with the CC genotypes to control body weight and consequently to reduce the risk for T2DM.

Consistent with the above observation, in the LIPGENE (Diet, Genomics, and the Metabolic Syndrome: an Integrated Nutrition, Agrofood, Social, and Economic Analysis) dietary intervention study involving 451 over weight subjects (average BMI 32.4) from 8 European countries, an interaction between ADIPOQ - 11377 C>G polymorphism with serum SFA level was also detected. The CC genotypes had an elevated insulin resistance when their serum SFA level is more than 30.92% of total lipid while for the G allele carriers the insulin resistance remained the same.  An implication of this study therefore is to limit SFA intake for the CC genotypes (Ferguson et al, 2010).

There is no ADIOPO promoter region haplotype-dietary interaction study published in the literature. Never the less, it can be derived from the results for each individual SNP-dietary interaction studies and the haplotype effect on adiponectin levels, that for the G-G haplotype (the T2DM risk haplotype) and G-C haplotype carriers, low-fat high-carbohydrate and increased MUFAs diets are recommended. For the promoter region A-C haplotype carriers, high-MUFA diets are beneficial.

Shin et al (2006) investigated the effects of gene region haplotypes on weight loss by 12 weeks of calorie restriction in non-diabetic and overweight–obese Korean subjects. After 12 weeks of caloric restriction, significant differences in the magnitude of adiponectin levels changes were detected among different haplotypes.  The adiponectin increased the most in T-G/T-G haplotype genotype (0.38μg/ml), followed by the genotypes contain one T-G copy (T-G/X-X, 0.26μg/ml).  In haplotype genotype that does not contain any T-G haplotype, the adiponectin level was actually decreased (-0.33μg/ml) by calorie restriction (Shin et al, 2006).

The gene region haplotype-dietary interaction was investigated in another interventional study involving 363 Korean subjects with impaired fasting glucose (IFG) or newly diagnosed type 2 diabetes.  The intervention included the dietary replacement of high glycemic index food (cooked refined rice) with low glycemic index food (whole grains and an increase in vegetable intake) and active life style (regular walking) for 12 weeks without any medication. After the intervention, the greatest decrease in insulin resistance indexes and the greatest increase in adiponectin levels were shown in overweight and obese subjects with the T-G/T-G haplotype genotypes (Chung et al, 2009). These results indicate that the T-G haplotype is susceptible to obesity induced insulin resistance due to excess calorie intake and that these harmful effects can be reverted by calorie restriction and weight loss.

Overall, the risk haplotypes (promoter region G-G and gene region T-G) exhibit lower adiponectin level. Carriers of these haplotypes should avoid high-fat (especially saturated fat) and high glycemic index food. Calorie restriction is the most effective way to lose weight for these haplotype carriers.  For the haplotypes exhibiting increased adiponectin level (e.g. promoter region A-C and gene region G-G), high-MUFA diet are most beneficial to the carriers.

Summary

Since it was discovered in 1995, adiponectin and its gene ADIPOQ have been intensively studied for their roles in obesity and insulin resistance.  Besides the SNPs and haplotypes mentioned here, many other ADIPOQ gene polymorphisms are being added on to the list of obesity and T2DM risk related SNPs.  Adiponectin is also becoming appreciated for its protective role in cardiovascular and its anti-inflammatory function. Based on our knowledge today, the most representative haplotypes that are interacting with dietary factors and are associated with obesity induced insulin resistance are the promoter region G-G and gene region T-G haplotypes.  Calorie restriction, diet fat content and diet fat composition are the most effect factors to consider in ADIPOQ gene based health management.

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