Abstract
Objective. Adiponectin is an anti-diabetic, anti-atherogenic, anti-inflammatory, and angiogenic adipokine that circulates in oligomeric complexes including: low molecular weight (LMW) trimers, medium molecular weight (MMW) hexamers, and high molecular weight (HMW) isoforms. The aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight.
Study design. In this cross-sectional study, plasma concentrations of total, HMW, MMW, and LMW adiponectin were determined in women included in three groups: (1) normal pregnant women of normal body mass index (BMI) (n = 466), (2) overweight pregnant women (BMI ≥25; n = 257), and (3) non-pregnant women of normal weight (n = 40). Blood samples were collected once from each woman between 11 and 42 weeks of gestation. Plasma adiponectin multimer concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Non-parametric statistics were used for analysis.
Results. (1) The median HMW adiponectin concentration and the median HMW/total adiponectin ratio were significantly higher, and the median LMW adiponectin concentration was significantly lower in pregnant women than in non-pregnant women. (2) Among pregnant women, the median plasma concentration of total, HMW, and MMW adiponectin was significantly higher in normal weight women than in overweight patients. (3) Maternal HMW was the most prevalent adiponectin multimer regardless of gestational age or BMI status. (4) There were no significant differences in the median concentration of total, MMW, and LMW adiponectin and their relative distribution with advancing gestation.
Conclusion. Human pregnancy is characterized by quantitative and qualitative changes in adiponectin multimers, especially the most active isoform, HMW adiponectin.
Introduction
Insulin resistance is one of the hallmarks of human pregnancy Citation[1-14]. Teleologically, an increased maternal resistance to insulin and the amplified production of glucose are aimed to ensure adequate glucose transport to the developing fetus Citation[15-17]. The ephemeral nature of this metabolic alteration during pregnancy, as well as empirical findings Citation[18-24], led to the conventional view that this physiologic adaptation stems from the ‘diabetogenic’ effect of the placental hormones.
Adipose tissue has emerged as a powerful endocrine organ Citation[25-37] that can exert autocrine, paracrine, and endocrine effects by the production and secretion of a variety of adipokines including adiponectin Citation[38-46], leptin Citation[6],Citation[47-51], tumor necrosis factor (TNF)-αCitation[46],Citation[52-55], and resistin Citation[56-60]. These highly active peptides and proteins Citation[30,31],Citation[61,62] have been implicated in the pathophysiology of the most common metabolic complications such as insulin resistance Citation[25],Citation[63-70], obesity Citation[71-75], and the metabolic syndrome Citation[43],Citation[70],Citation[76-81]. An abundance of evidence demonstrates that adipokines play an important role in the metabolic homeostasis during normal gestation Citation[82-89], as well as in complications of pregnancy such as gestational diabetes mellitus (GDM) Citation[63],Citation[90-100] and preeclampsia Citation[101-112].
Adiponectin, identified independently by four groups Citation[40],Citation[42],Citation[44,45], is the most abundant gene (AMP1) product of adipose tissue; it circulates at relatively high concentrations Citation[38],Citation[40],Citation[71],Citation[74],Citation[113,114] and accounts for 0.01% of the total plasma proteins. The plasma concentrations of adiponectin are paradoxically lower in obese than in non-obese individuals Citation[38],Citation[40]. In addition, weight reduction is associated with an increase in plasma adiponectin concentration Citation[72],Citation[74], suggesting that adipose tissue exerts a negative feedback on adiponectin production or secretion. Adiponectin has an important role in the pathophysiology of insulin resistance and diabetes Citation[115-122], atherosclerosis Citation[77-79],Citation[123,124], hypertension Citation[80],Citation[125,126], dyslipidemia Citation[127-129], and angiogenesis Citation[130,131]. Moreover, adiponectin has been suggested to play a regulatory role in the metabolic adaptation during human pregnancy Citation[25],Citation[65],Citation[83,84], as well as in the pathophysiology of GDM Citation[90],Citation[92-94],Citation[96] and preeclampsia Citation[101-109].
Adiponectin circulates in human plasma in distinct forms: (1) low molecular weight (LMW) trimers, (2) medium molecular weight (MMW) hexamers, and (3) high molecular weight (HMW) oligomers (12 to 18 subunits) Citation[38],Citation[45],Citation[132-138]. These adiponectin multimers can exert distinct biological effects Citation[133-140], activate different single transduction pathways Citation[133],Citation[138], and may have different affinities to the adiponectin receptors Citation[141]. In particular, the adiponectin sensitivity index (SA) Citation[137], which is the ratio of HMW to total adiponectin, has been reported to be a more sensitive marker of the biological activity of adiponectin Citation[134,135],Citation[137],Citation[139,140],Citation[142-161]. Indeed, SA has a better correlation with insulin resistance Citation[134,135],Citation[137],Citation[140],Citation[142-146], obesity Citation[147-150], cardiovascular diseases Citation[134],Citation[139],Citation[151,152], and other impaired metabolic states Citation[153-161] than total adiponectin.
Only a handful of studies have addressed the changes in maternal adiponectin multimer concentrations and their relative concentration during human pregnancy Citation[25],Citation[162-165]. Moreover, data regarding the concentrations of the HMW, MMW, and LMW adiponectin isoforms in each trimester and the association between maternal weight and the relative distribution of adiponectin multimers has not been reported. Thus, the aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight.
Materials and methods
Study design and population
A cross-sectional study was conducted using samples and data retrieved from the bank of biological samples and clinical database of the Perinatology Research Branch of the National Institute of Child Health and Human Development (NICHD). The following groups of subjects were included: (1) normal pregnant women of normal body mass index (BMI) (n = 466), (2) overweight pregnant women with normal pregnancy (n = 257), and (3) non-pregnant women (n =40) without any prior or current medical or metabolic conditions who were not using oral contraceptives.
The inclusion criteria for normal pregnant women were: singleton gestation, no prior diabetes mellitus, no maternal or fetal complications during pregnancy, normal plasma glucose concentrations in the first trimester, normal oral glucose challenge test, and delivery at term of a healthy neonate with a birth weight above the 10th percentile for gestational age. Maternal blood samples were collected once from each woman at the following gestational ages: 11–14 weeks (n = 84), 15–18 weeks (n = 93), 19–22 weeks (n = 93), 23–26 weeks (n = 94), 27–30 weeks (n = 95), 31–34 weeks (n = 96), and term (≥37 weeks) in labor (n = 98) and not in labor (n = 80). BMI was calculated according to the formula: weight (kg)/height (m2). Normal weight women were defined as those with a BMI of 18.5–25 kg/m2 according to the definitions of the World Health Organization (WHO) Citation[166]. Pregnant women were classified by their first trimester BMI into two groups: normal weight and overweight (BMI ≥25 kg/m2) and by the gestational age at sample collection.
Written informed consent was obtained from all participants after approval by the Institutional Review Board of both the Sotero del Rio Hospital (Chile) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (Bethesda, MD, USA).
Sample collection
Blood was collected in vials containing ethylenediaminetetraacetic acid and centrifuged at 1300 ×g for 10 min at 4°C. The plasma was stored at −80°C until analysis. Many of these samples have been used previously to study the biology of inflammation, hemostasis, angiogenesis regulation, and growth factor concentrations in non-pregnant and normal pregnant women.
Quantitative determination of multimeric forms of adiponectin in maternal plasma
Sensitive enzyme-linked immunoassays were used to determine the concentrations of adiponectin multimeric forms in maternal plasma. Immunoassays were purchased from ALPCO Diagnostics (Salem, NH, USA). The assays were run according to the recommendations of the manufacturer. To detect HMW adiponectin, plasma samples were pretreated with a specific protease that selectively digests MMW and LMW adiponectin. We were also able to determine the combined HMW and MMW adiponectin concentrations by pretreating the samples with a protease that specifically digests LMW adiponectin. Maternal plasma samples were assayed directly to determine total adiponectin concentrations. Briefly, untreated and pretreated maternal plasma samples were incubated in duplicate wells of the microtiter plates, which had been pre-coated with a monoclonal antibody specific for adiponectin. During this incubation any adiponectin present in the standards and untreated or pretreated maternal plasma samples was bound by the immobilized antibodies. After repeated washing and aspiration to remove all unbound substances, an enzyme-linked polyclonal antibody specific for adiponectin was added to the wells. Unbound materials were removed with repeated washing and a substrate solution was added to the wells and color developed in proportion to the amount of adiponectin bound in the initial step. The color development was stopped with the addition of an acid solution and the intensity of color was read using a programmable spectrophotometer (SpectraMax M2, Molecular Devices, Sunnyvale, CA, USA). The concentration of adiponectin in untreated and treated maternal plasma samples was determined by interpolation from individual standard curves composed of human adiponectin. Total, HMW, and HMW–MMW adiponectin concentrations were derived directly from the assay plates. MMW adiponectin concentrations were obtained by subtracting the HMW adiponectin value from the combined HMW–MMW value. Finally, the LMW adiponectin value was computed by subtracting HMW and MMW adiponectin values from the total adiponectin values. The calculated inter- and intra-assay coefficients of variation for adiponectin multimer immunoassays in our laboratory were 2.2% and 4.2%, respectively. The sensitivity was calculated to be 0.04 ng/mL.
Statistical analysis
Normality of the data was tested using Shapiro–Wilk or Kolmogorov–Smirnov tests. Plasma multimeric adiponectin isoform concentrations were not normally distributed, thus non-parametric methods were used to perform the statistical analysis. Correlation between the various adiponectin multimers and gestational age, maternal age, BMI, and birth weight was conducted with Spearman's rank correlation.
Comparison of the median concentration of adiponectin multimers among the gestational age groups was performed by Kruskal–Wallis test with post-hoc analyses by Mann–Whitney U-test with Bonferroni correction for the calculated p-value in order to maintain the significance level at 0.05.
Results
displays the maternal demographic and clinical characteristics of all pregnant women according to BMI. Overweight pregnant women were older compared to normal weight pregnant women. There were no significant differences in parity, gestational age at sampling, or gestational age at delivery between normal weight and overweight women. displays the maternal demographic and clinical characteristics of the normal and overweight pregnant women according to the different gestational age groups. There were no significant differences in maternal age, parity, BMI, or gestational age at delivery between the various gestational age groups.
Table I. Clinical characteristics of normal weight and overweight pregnant women.
Table II. Demographic and clinical characteristics of normal weight and overweight pregnant women according to gestational age at sampling.
When all pregnant women were pooled together, total adiponectin concentrations were negatively correlated with gestational age at sampling (r = −0.11, p < 0.01). HMW adiponectin concentrations were negatively correlated with BMI at sampling only in overweight patients (r = −0.15, p = 0.01). The HMW/total adiponectin ratio was negatively correlated with BMI at sampling in both normal weight (r = −0.10, p = 0.03) and overweight (r = −0.12, p = 0.04) pregnant women.
Reference tables of the normal plasma adiponectin concentrations for each gestational age, including the 10th, 25th, 50th, 75th, and 90th percentiles, in normal weight and overweight pregnant women, are presented in and , respectively.
Table III. Plasma total, HMW, MMW, and LMW adiponectin concentrations (ng/mL) in normal weight pregnant women.
Table IV. Plasma total, HMW, MMW, and LMW adiponectin concentrations (ng/mL) in overweight pregnant women.
Adiponectin multimer concentrations and relative distribution in non-pregnant vs. pregnant women
When all pregnant women were pooled together (except those in labor), the median maternal concentration of HMW adiponectin was significantly higher in pregnant women than in non-pregnant women (median 3554 ng/mL, range 52–17 548 ng/mL vs. median 2812 ng/mL, range 801–8937 ng/mL; p = 0.01). Similarly, pregnant women had a higher median HMW/total adiponectin ratio than non-pregnant women (median 56.3%, range 2–88% vs. median 46.0%, range 25–81%, respectively; p < 0.01). In contrast, the median maternal plasma concentration of LMW adiponectin was lower in pregnant than non-pregnant women (median 1235 ng/mL, range 56–6112 ng/mL vs. median 1883 ng/mL, range 766–3976 ng/mL; p < 0.01). The median maternal plasma concentrations of total and MMW adiponectin did not differ between the two groups.
The median total adiponectin concentration was comparable between the different gestational age groups. Similarly, the median ratio of HMW, MMW, and LMW to total adiponectin did not change significantly with advancing gestation. The median HMW adiponectin concentration was significantly higher than the median concentrations of MMW (p < 0.01) and LMW (p < 0.01) adiponectin at any gestational age. The median concentrations of MMW and LMW adiponectin did not differ with advancing gestation.
Among non-pregnant women, the median HMW adiponectin concentration was significantly higher than the median adiponectin concentrations of MMW and LMW adiponectin (p < 0.01, for both comparisons). The median concentration of LMW was significantly higher than the median plasma MMW adiponectin concentration (p<0.01) ().
Figure 1. Comparison of the median plasma total, HMW, MMW, and LMW adiponectin concentrations between non-pregnant, normal weight, and overweight pregnant women. The median plasma concentration of total, HMW, and MMW adiponectin was significantly higher in normal weight than overweight women. Among non-pregnant women, the median HMW adiponectin concentration was significantly higher than the median concentrations of MMW and LMW adiponectin. The median concentration of the latter was significantly higher than MMW adiponectin.
Changes in adiponectin multimer plasma concentrations of non-pregnant and pregnant women
Compared to non-pregnant women, normal weight pregnant women had a higher median concentration of HMW adiponectin (median 3949 ng/mL, range 945–17 548 ng/mL vs. median 2812 ng/mL, range 801–8937 ng/mL; p < 0.01) and a lower median concentration of LMW adiponectin (median 1217 ng/mL, range 56–6112 ng/mL vs. median 1883 ng/mL, range 766–3976 ng/mL; p < 0.01). In contrast, overweight patients had only a lower median concentration of LMW adiponectin than non-pregnant women (median 1260 ng/mL, range 85–4009 ng/mL vs. median 1883 ng/mL, range 766–3976 ng/mL; p < 0.01).
Compared to overweight pregnant women, those with normal weight had higher median plasma concentrations of total adiponectin (median 6792 ng/mL, range 2442–21 956 ng/mL vs. median 5577 ng/mL, range 2180–16 301 ng/mL; p < 0.01, ), HMW adiponectin (median 3949 ng/mL, range 945–17 548 ng/mL vs. median 2934 ng/mL, range 52–11 954 ng/mL; p < 0.01), and MMW adiponectin (median 1452 ng/mL, range 220–5158 ng/mL vs. median 1280 ng/mL, range 174–11 272 ng/mL; p < 0.01, ). The median concentrations of LMW adiponectin were comparable between normal weight and overweight pregnant women (1217 ng/mL, range 56–6112 ng/mL vs. 1260 ng/mL, range 85–4009 ng/mL, respectively; p = 0.7).
The relative distribution of adiponectin multimers in normal weight and overweight pregnant women
The median HMW/total adiponectin ratio was higher in normal weight than in overweight pregnant women (median 57.3%, range 33–86% vs. median 53.1%, range 2–88%; p < 0.01). This ratio was also higher in overweight patients compared to non-pregnant women (median 53.1%, range 2–88% vs. median 46.0%, range 25–81%; p < 0.01) (). In contrast, the LMW to total adiponectin ratio was higher in non-pregnant women than in overweight pregnant women (median 33.3%, range 10–53% vs. median 21.9%, range 1–83%; p < 0.01) and in the latter group compared to normal weight pregnant women (median 21.9%, range 1–83% vs. median 19.3%, range 1–83%; p < 0.01) ().
Figure 2. Comparison of HMW/total adiponectin, MMW/total adiponectin, and LMW/total adiponectin between non-pregnant, normal weight, and overweight pregnant women. The median HMW/total adiponectin ratio was significantly higher in normal weight than overweight pregnant women and in overweight patients compared to non-pregnant women. The median LMW/total adiponectin ratio was significantly higher in non-pregnant women than the median LMW/total adiponectin ratio in normal weight and overweight pregnant women. The median LMW/total adiponectin ratio was significantly higher in overweight pregnant than in normal weight women.
Adiponectin multimer concentrations and their relative distribution with advancing gestation in normal and overweight pregnant women
The median maternal plasma concentration of total adiponectin was higher in normal weight than overweight women at 11–14 weeks of gestation (median 6578 ng/mL, range 3293–18 887 ng/mL vs. median 5831 ng/mL, range 2180–12 554 ng/mL; p = 0.02, ), 19–22 weeks of gestation (median 6697 ng/mL, range 3446–21 954 ng/mL vs. median 5868 ng/mL, range 2909–14 988 ng/mL; p = 0.01, ), and 31–34 weeks of gestation (median 7304 ng/mL, range 3415–16 504 ng/mL vs. median 5056 ng/mL, range 3060–11 260 ng/mL; p = 0.01, ).
Figure 3. Maternal plasma (a) total adiponectin, (b) HMW adiponectin, (c) MMW adiponectin, and (d) LMW adiponectin concentrations in normal weight and overweight women according to gestational age groups. Among women at 11–14 weeks of gestation, normal weight women had a higher median concentration of total (3a) and HMW (3b) adiponectin than overweight patients. Among women at 19–22 weeks of gestation, normal weight women had a higher median concentration of total (3a), HMW (3b), and MMW (3c) adiponectin than overweight patients. Among women at 31–34 weeks of gestation, normal weight women had a higher median concentration of total (3a), HMW (3b), and MMW (3c) adiponectin than overweight patients. Among women at term, normal weight women had a higher median concentration of HMW (3b) adiponectin than overweight patients.
The median maternal plasma concentration of HMW adiponectin was higher in normal weight than overweight women at 11–14 weeks of gestation (median 3961 ng/mL, range 1281–13 384 ng/mL vs. median 2723 ng/mL, range 412–6584 ng/mL; p < 0.01, ), 19–22 weeks of gestation (median 3674 ng/mL, range 1462–17 548 ng/mL vs. median 2795 ng/mL, range 52–11 954 ng/mL; p < 0.01, ), 31–34 weeks of gestation (median 4084 ng/mL, range 1553–14 196 ng/mL vs. median 2672 ng/mL, range 372–7592 ng/mL; p = 0.01, ), and at term (median 3916 ng/mL, range 945–7928 ng/mL vs. median 2946 ng/mL, range 1423–8589 ng/mL; p = 0.01, ).
The median maternal plasma concentration of MMW adiponectin was higher in normal weight than overweight women at 19–22 weeks of gestation (median 1467 ng/mL, range 268–4644 ng/mL vs. median 1171 ng/mL, range 263–2559 ng/mL; p < 0.01, ) and at 31–34 weeks of gestation (median 1551 ng/mL, range 552–4227 ng/mL vs. median 1204 ng/mL, range 322–2129 ng/mL; p < 0.01, ).
The median maternal HMW/total adiponectin ratio was higher in normal weight than overweight women at 11–14 weeks of gestation (median 58.5%, range 33–76% vs. median 51.1%, range 18–81%; p < 0.01, ) and at 19–22 weeks of gestation (median 57.7%, range 40–82% vs. 52.2%, range 2–82%; p = 0.03, ).
Figure 4. Comparison of HMW/total adiponectin, MMW/total adiponectin, and LMW/total adiponectin between normal weight and overweight pregnant women at (a) 11–14 weeks of gestation and (b) 19–22 weeks of gestation. The median HMW/total adiponectin ratio was higher in normal weight than in overweight pregnant women at 11–14 weeks (4a) and 19–22 weeks (4b) of gestation.
The effect of labor on adiponectin multimer concentrations
Women at term in labor had a higher median concentration of HMW adiponectin compared to women at term not in labor (median 4051 ng/mL, range 182–9204 ng/mL vs. median 3392 ng/mL, range 945–8589 ng/mL; p = 0.02, ). In addition, labor was associated with an increased median HMW/total adiponectin ratio (median 58.6%, range 6–82% vs. median 53.9%, range 34–75%; p = 0.01) and a decreased LMW to total adiponectin ratio (median 17.7%, range 3–83% vs. median 20.0%, range 2–39%; p = 0.03).
Among pregnant women at term, in labor and not in labor, the median plasma concentration of HMW adiponectin was higher than the median concentrations of LMW (p < 0.01) and MMW (p < 0.01) adiponectin. The latter was higher than the median LMW adiponectin concentrations (p < 0.01) ().
Figure 5. Comparison of median plasma total, HMW, MMW, and LMW adiponectin concentrations between women at term in labor and not in labor. Women at term in labor had a higher median concentration of HMW adiponectin compared to women at term not in labor. Among pregnant women in labor and not in labor at term, the median plasma concentration of HMW adiponectin was higher than the median concentrations of LMW and MMW adiponectin. The latter was higher than the median LMW adiponectin concentrations.
Normal weight women at term not in labor had a higher median concentration of HMW adiponectin than overweight patients. Among women in labor, those with normal weight had a higher median concentration of total adiponectin (median 7080 ng/mL, range 2844–13 701 ng/mL vs. median 5983 ng/mL, range 2395–11 367 ng/mL; p < 0.01), HMW adiponectin (median 4405 ng/mL, range 182–9204 ng/mL vs. median 3358 ng/mL, range 1046–8130 ng/mL; p = 0.01), and MMW adiponectin (median 1657 ng/mL, range 288–2772 ng/mL vs. median 1331 ng/mL, range 388–2796 ng/mL; p = 0.03) than overweight women.
Discussion
Principal findings of the study
(1) HMW was the most prevalent adiponectin isoform, regardless of gestational age or BMI status. (2) The median HMW adiponectin concentration and HMW/total adiponectin ratio were significantly higher, and the median LMW adiponectin concentration was lower, in pregnant compared to non-pregnant women. (3) Among pregnant women, the median concentration of total, HMW, and MMW adiponectin were significantly higher in normal weight compared to overweight women. (4) The median concentrations of total, MMW, and LMW adiponectin as well as their relative distribution were comparable for each gestational age group.
What is the rationale to assess maternal circulating adiponectin?
Adiponectin is a member of a growing group of peptides and proteins secreted by adipose tissue, termed adipokines. In contrast to the other adipokines whose concentrations increase with the accumulation of fat mass, adiponectin concentrations are lower in overweight and obese patients compared to normal weight subjects Citation[38],Citation[40],Citation[84],Citation[167,168]. The insulin sensitizing Citation[115,116],Citation[121],Citation[169-174], anti-atherogenic Citation[78-80],Citation[124],Citation[175-178], and the anti-inflammatory Citation[126],Citation[179-183] properties of adiponectin, have provided a mechanistic basis for the association between adiposity and metabolic complications. Indeed, low adiponectin concentrations have been reported in type 2 diabetes mellitus and insulin resistance Citation[115-122],Citation[182],Citation[184-189], cardiovascular disease Citation[118],Citation[190,191], dyslipidemia Citation[70],Citation[81],Citation[192-198], and atherosclerosis Citation[43],Citation[78,79],Citation[123,124],Citation[139],Citation[175,176],Citation[199,200]. Thus, the concept of the protective role of adiponectin has evolved Citation[41],Citation[46],Citation[201-204].
Several factors prompted the investigation of adiponectin in human pregnancy: (1) the unique combination of its biological properties, including insulin sensitizing Citation[115,116],Citation[121],Citation[169-174], anti-atherogenic Citation[78-80],Citation[124],Citation[175-178], anti-inflammatory Citation[126],Citation[179-183], and anti-angiogenic Citation[130,131],Citation[205-207] effects; (2) physiological adaptation to pregnancy is characterized by insulin resistance Citation[1-12],Citation[14] and remarkable fat depot Citation[208-213]; and (3) the association between insulin resistance and increased adipose depots and angiogenesis in common pregnancy complications such as gestational diabetes Citation[209,210],Citation[214-217] and preeclampsia Citation[217-224].
The role of adiponectin in human pregnancy
A solid body of evidence supports the role of adiponectin in normal gestation and pregnancy complications: (1) circulating maternal adiponectin correlates with insulin resistance indices during pregnancy Citation[25],Citation[64-66]; (2) patients with GDM have lower concentrations of adiponectin compared to those without GDM Citation[90],Citation[92-94],Citation[96]; (3) women with adiponectin concentrations less than 6.4 μg/mL in the first or early second trimester experienced a 4.6-fold increased risk of GDM compared to those with higher concentrations Citation[95]; (4) overweight pregnant patients have a lower adiponectin concentration than normal weight pregnant women Citation[84]; and (5) preeclampsia is associated with altered maternal adiponectin concentrations. Both higher Citation[101],Citation[104-109] and lower Citation[102],Citation[225,226] adiponectin concentrations in patients with preeclampsia compared to normal pregnant women have been reported. Collectively, these findings suggest that adiponectin may play a regulatory role in metabolic and vascular complications of pregnancy.
Multimerization as a method of regulation: Adiponectin isoforms regulate its pleiotropic effect
The structural diversity of adiponectin multimers has been proposed to be associated with its pleiotropic effect. Structurally, adiponectin belongs to the complement 1q family, which is known to form characteristic multimers Citation[227-229]. This adipokine undergoes post-translational modification Citation[230,231] within the adipocytes into multimeric forms, including LMW trimers, MMW hexamers, and HMW oligomers (12–18 monomers) Citation[44,45],Citation[132,133],Citation[136],Citation[138],Citation[232]. None of the multimeric forms interchange with each other after secretion, neither in vivo nor in vitroCitation[136]. It has been suggested that the various adiponectin isoforms have distinct biological activities: (1) in vitro, HMW and MMW adiponectin have pro-inflammatory properties such as induction of interleukin (IL)- 6 from human monocytes and activation of nuclear factor (NF)-κB Citation[138],Citation[233-235], whereas LMW adiponectin inhibits the release of IL-6 Citation[160],Citation[236], a pro-inflammatory cytokine, and increases the secretion of IL-10 Citation[236], an anti-inflammatory cytokine. In addition, only HMW adiponectin has been shown to suppress apoptosis of endothelial cells Citation[139]. (2) MMW and HMW can activate NF-κB, while LMW adiponectin activates AMP-activated protein kinase (AMPK) in skeletal muscle Citation[138]. These findings represent a novel paradigm where multimerization state of a hormone can regulate a specific signaling. (3) Administration of HMW, but not LMW, adiponectin multimers to adiponectin knock-out mice results in a dose-dependent reduction in serum glucose concentrations Citation[137]. (4) Mutations in the collagen domain are associated with type 2 diabetes mellitus and extremely low concentrations of HMW adiponectin Citation[117],Citation[133],Citation[237]. (5) The plasma HMW/total adiponectin ratio has a better correlation with insulin resistance indices (e.g., HOMA-IR) compared to total adiponectin concentrations, and the HMW/total adiponectin ratio is lower in patients with diabetes compared to non-diabetic subjects Citation[137],Citation[139],Citation[142],Citation[144],Citation[146],Citation[157]. (6) Absolute concentrations of HMW have a better correlation with metabolic indices (e.g., HDL cholesterol and total cholesterol concentrations) and endothelial dysfunction than total adiponectin Citation[135],Citation[155],Citation[165],Citation[238,239]. Thus, HMW adiponectin concentrations may be the superior biomarker for insulin resistance and the metabolic syndrome. (7) Weight reduction and treatment with insulin sensitizing drugs (e.g., thiazolidinedione) preferentially elevates the HMW adiponectin compared to the other two isoforms Citation[137],Citation[139,140] or to total adiponectin concentration Citation[149,150],Citation[152]. In addition, refeeding of patients with anorexia nervosa has been found to be associated with a decrease in HMW adiponectin concentrations Citation[158],Citation[240].
Collectively, these data suggest that multimerization of adiponectin plays an important role in its metabolic and anti-inflammatory functions. In addition, those reports highlight the importance of the relative distribution of adiponectin multimers as more precise determinants governing adiponectin's protective properties against metabolic inflammatory and atherogenic disorders.
Determination of circulating adiponectin multimers: The pros and cons of the available methods
Several methods have been developed to identify and measure the various adiponectin isoforms. Gel filtration chromatography Citation[38],Citation[132],Citation[136] and SDS–PAGE Citation[133],Citation[137,138] have been used. Recently, an ELISA assay specific to adiponectin multimers has been developed Citation[241-243]. ELISA has several advantages over the previously used methods: (1) formerly, determination of circulating adiponectin multimers was only semi-quantitative and required size fraction by velocity sedimentation followed by SDS–PAGE and Western blotting Citation[135],Citation[137],Citation[139],Citation[155],Citation[244]; (2) although reproducible, those methods are time consuming and laborious and thus essentially preclude clinical implantation of their use. The use of ELISA, on the other hand, is accurate, does not involve special pre-treatment of the sample and negates the need for arduous laboratory work Citation[241-243]. The current literature indicates that adiponectin isoforms may differ in their biological activity, and therefore, to better understand the effects of this hormone, not only the absolute amount but also the distribution of its isoforms has to be considered. Applications of the measurements of the different adiponectin isoforms in maternal plasma have been limited, mostly due to the lack of high-throughput assays. However, the new ELISA assays provide a potential solution to this limitation.
Human pregnancy is characterized by quantitative and qualitative alterations in adiponectin concentration
Only a handful of studies have addressed the maternal adiponectin multimer concentrations and relative distributions Citation[25],Citation[162-165]. Catalano et al. Citation[25] conducted a longitudinal study in which total, HMW, and LMW adiponectin were measured in 10 normal lean women, before pregnancy, in early gestation (12–14 weeks), and in late gestation (34–36 weeks). The authors reported that maternal plasma HMW adiponectin and HMW/total adiponectin ratio were lower in late gestation than in the non-pregnant state and there were no significant differences in circulating adiponectin multimers between early and late gestation. Ong et al. Citation[162] found a negative correlation between third trimester HMW/total adiponectin ratio and birth weight in 58 patients. In addition, changes in maternal adiponectin multimer concentrations were reported in complicated pregnancy. Retnakaran et al. Citation[165] reported a lower HMW adiponectin concentration in patients with GDM (n = 41) compared to third trimester normal pregnant women (n = 80). In a study conducted by the same group Citation[163] the HMW/total adiponectin ratio, measured between 28 and 31 weeks of gestation, is decreased in pregnant women of Indo-Asian descent (n = 30) compared with Caucasian women (n = 65). Takemura et al. Citation[164] described higher maternal concentrations of HMW adiponectin and higher HMW/total adiponectin ratios in patients with preeclampsia (n = 14) compared to normal pregnant women (n = 14). Of note, the ELISA assay was used only in the latter study.
Our findings reported herein are in accordance with previous studies in which total adiponectin concentration did not differ between the pregnant and non-pregnant women Citation[65],Citation[84],Citation[102],Citation[245]. However our results indicate that pregnancy is associated with a higher median HMW adiponectin concentration and HMW/total adiponectin ratio, as well as a lower median LMW adiponectin concentration than the non-pregnant state. The discrepancy in the findings reported herein and those previously reported Citation[25] may result from differences in the study design, definition of adiponectin multimers, and methods to determine plasma adiponectin isoforms. In particular, our study was cross-sectional, included a higher number of women at a wide range of gestational ages, both lean and overweight, determined the adiponectin total concentrations and its isoforms by ELISA assay, and distinguished in the analysis between MMW and LMW adiponectin isoforms.
Human pregnancy is characterized by a shift from LMW adiponectin to HMW adiponectin
The increase in the median HMW adiponectin concentration and the median HMW/total adiponectin ratio and the parallel decrease in the median LMW adiponectin concentration in pregnant compared to non-pregnant women are novel. There can be several explanations for these findings:
Compensatory reaction to metabolic alterations of pregnancy
The shift from LMW adiponectin to HMW adiponectin and the consequently higher HMW/total adiponectin ratio in the pregnant compared to the non-pregnant state may represent a compensatory response. Human pregnancy may be viewed as a forme fruste of the metabolic syndrome, as the maternal physiological adaptation to normal pregnancy includes core components of this condition including: weight gain and increase in fat deposition Citation[25],Citation[208-213], hyperlipidemia Citation[246-249], and insulin resistance Citation[1-14]. The current literature indicates that HMW adiponectin has a prominent protective role, particularly against metabolic complications such as insulin resistance Citation[137],Citation[142],Citation[144],Citation[146],Citation[155],Citation[157],Citation[239] and hyperlipidemia Citation[135],Citation[152],Citation[238]. Total adiponectin concentrations are comparable between non-pregnant and pregnant women. However, gestation is characterized by a shift from a less active (LMW) to a more active isoform (HMW) of adiponectin suggesting that the higher HMW adiponectin concentrations may be a counter-regulatory response to the metabolic changes (e.g., insulin resistance, hyperlipidemia) associated with normal pregnancy.
Adipogenesis during pregnancy favors production and secretion of HMW adiponectin
An alternative explanation for the higher HMW adiponectin observed in normal pregnancy can be the significant weight gain and increased fat depot that accompanies normal gestation Citation[25],Citation[208-213]. Previously, the mechanism for increased fat mass in normal and obese individuals has been attributed exclusively to adipocyte hypertrophy; however, adipose tissue accretion during pregnancy is now know to be associated also with adipocyte hyperplasia Citation[250-255]. This finding is supported by reports demonstrating the effect of peroxisome proliferator-activated receptor (PPAR)-γ agonist on adipose tissue. Treatment with a PPAR-γ agonist (e.g., thiazolidinediones), results in a distinct increase in the number of newly differentiated small adipocytes Citation[256], as well as body weight gain and increased plasma adiponectin concentrations Citation[232],Citation[257-263]. Treatment with a PPAR-γ agonist (in mice and humans) has resulted in a decreased insulin resistance and a dramatic increase in circulating adiponectin concentration, mostly due to the elevation in HMW adiponectin Citation[137],Citation[140]. In conclusion, adipogenesis may contribute to the shift towards HMW adiponectin in pregnant women. It is important to note in this context that the major role of the HMW multimers has been highlighted in the context of the effect of PPAR-γ.
Adiponectin multimer concentration with advancing gestation
When normal weight and overweight patients were pooled together, the median total adiponectin concentration and the median concentration of adiponectin multimers and their relative distribution did not change with advancing gestational age. HMW adiponectin was the most prevalent adiponectin species regardless of gestational age or BMI. These finding are in agreement with the findings of Catalano et al. Citation[25] in which maternal HMW and LMW adiponectin concentrations did not differ between 12–14 and 34–36 weeks of gestation. This report extends the available data by showing comparable concentrations of adiponectin with advancing gestation. Moreover, the nomogram ( and ) presented herein should be beneficial to those investigating the intriguing relationships between adiponectin multimers and human pregnancy.
The perils of portliness: Maternal overweight is associated with decreased HMW adiponectin
The contribution of excess body weight to the concentration of adiponectin multimers and their relative distribution by comparing the concentrations of adiponectin species in normal weight and overweight pregnant women is reported herein. Consistent with the non-pregnant state Citation[38],Citation[40],Citation[84],Citation[167,168], normal weight women had higher median total, HMW, and MMW adiponectin concentrations than overweight patients. In contrast to normal weight pregnant women who had higher HMW adiponectin compared to non-pregnant subjects, the median concentration of HMW adiponectin was comparable between overweight pregnant patients and non-pregnant women. The median HMW/total adiponectin ratio was significantly higher in normal weight compared to overweight pregnant women. In addition, overweight pregnant women had a distinct median concentration and relative distribution of adiponectin multimers with advancing gestation: at 11–14, 19–22, and 31–34 weeks of gestation and at term. Specifically, higher median concentrations of HMW and MMW adiponectin were detected in normal weight compared to overweight pregnant women.
Lower concentrations of total adiponectin in overweight pregnant women have been recently reported by our group Citation[84]. The results of the current study are also in agreement with previous reports regarding lower total adiponectin concentrations in overweight and obese non-pregnant patients Citation[38],Citation[40]. Contrary to other adipokines (e.g., leptin, TNF-α, and resistin), mRNA expression and plasma concentrations of adiponectin are paradoxically lower in overweight and obese than normal weight individuals Citation[38],Citation[40],Citation[120]; moreover, weight reduction is associated with an increase in circulating total Citation[72],Citation[74],Citation[264-267] and HMW adiponectin concentrations Citation[135],Citation[149],Citation[268]. In addition to obesity, the inverse relationship between this hormone and body weight is upheld in extremely lean subjects with anorexia nervosa Citation[158],Citation[269,270]. Taken together, these findings suggest that excess adipose tissue may exert a negative feedback on adiponectin production and/or secretion and may regulate the relative distribution of its multimers. The current study extends the heretofore studies by analyzing both the absolute and the relative distributions of HMW, MMW, and LMW adiponectin in the setting of normal weight and overweight pregnant women with advancing gestation and in labor.
In conclusion, the current report provides a comprehensive assessment of the interplay between the different adiponectin multimers in the maternal circulation during normal human pregnancy. Comparison of adiponectin species between non-pregnant and pregnant women and normal weight and overweight patients revealed quantitative and qualitative changes suggesting that adiponectin multimers, especially the most active isoform, HMW adiponectin, may play a role in the metabolic changes associated with pregnancy. Moreover, these findings, along with the nomograms presented herein, may lay the groundwork for further studies addressing the complex and intriguing relationships between body weight, adiponectin, and metabolic pathways in human pregnancy.
Acknowledgment
This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Buchanan T A, Metzger B E, Freinkel N, Bergman R N. Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol 1990; 162: 1008–1014
- Burt R L. Peripheral utilization of glucose in pregnancy. III. Insulin tolerance. Obstet Gynecol 1956; 7: 658–664
- Butte N F. Carbohydrate and lipid metabolism in pregnancy: Normal compared with gestational diabetes mellitus. Am J Clin Nutr 2000; 71: 1256S–1261S
- Catalano P M, Tyzbir E D, Roman N M, Amini S B, Sims E A. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 1991; 165: 1667–1672
- Catalano P M, Roman-Drago N M, Amini S B, Sims E A. Longitudinal changes in body composition and energy balance in lean women with normal and abnormal glucose tolerance during pregnancy. Am J Obstet Gynecol 1998; 179: 156–165
- Fisher P M, Sutherland H W, Bewsher P D. The insulin response to glucose infusion in normal human pregnancy. Diabetologia 1980; 19: 15–20
- Kuhl C. Glucose metabolism during and after pregnancy in normal and gestational diabetic women. 1. Influence of normal pregnancy on serum glucose and insulin concentration during basal fasting conditions and after a challenge with glucose. Acta Endocrinol (Copenh) 1975; 79: 709–719
- Langer O, Anyaegbunam A, Brustman L, Guidetti D, Mazze R. Gestational diabetes: Insulin requirements in pregnancy. Am J Obstet Gynecol 1987; 157: 669–675
- Lind T, Bell S, Gilmore E, Huisjes H J, Schally A V. Insulin disappearance rate in pregnant and non-pregnant women, and in non-pregnant women given GHRIH. Eur J Clin Invest 1977; 7: 47–52
- Phelps R L, Metzger B E, Freinkel N. Carbohydrate metabolism in pregnancy. XVII. Diurnal profiles of plasma glucose, insulin, free fatty acids, triglycerides, cholesterol, and individual amino acids in late normal pregnancy. Am J Obstet Gynecol 1981; 140: 730–736
- Reece E A, Homko C, Wiznitzer A. Metabolic changes in diabetic and nondiabetic subjects during pregnancy. Obstet Gynecol Surv 1994; 49: 64–71
- Ryan E A, O'Sullivan M J, Skyler J S. Insulin action during pregnancy. Studies with the euglycemic clamp technique. Diabetes 1985; 34: 380–389
- Spellacy W N, Goetz F C, Greenberg B Z, Ells J. Plasma insulin in normal ‘early’ pregnancy. Obstet Gynecol 1965; 25: 862–865
- Coustan D R, Carpenter M W. The diagnosis of gestational diabetes. Diabetes Care 1998; 21(Suppl 2)B5–8
- Buchanan T A, Xiang A H. Gestational diabetes mellitus. J Clin Invest 2005; 115: 485–491
- Kuhl C. Aetiology of gestational diabetes. Baillieres Clin Obstet Gynaecol 1991; 5: 279–292
- Ryan E A. Hormones and insulin resistance during pregnancy. Lancet 2003; 362: 1777–1778
- Barbour L A, Shao J, Qiao L, Pulawa L K, Jensen D R, Bartke A, Garrity M, Draznin B, Friedman J E. Human placental growth hormone causes severe insulin resistance in transgenic mice. Am J Obstet Gynecol 2002; 186: 512–517
- Beck P. Progestin enhancement of the plasma insulin response to glucose in Rhesus monkeys. Diabetes 1969; 18: 146–152
- Kalkhoff R K, Richardson B L, Beck P. Relative effects of pregnancy, human placental lactogen and prednisolone on carbohydrate tolerance in normal and subclinical diabetic subjects. Diabetes 1969; 18: 153–163
- Kalkhoff R K, Jacobson M, Lemper D. Progesterone, pregnancy and the augmented plasma insulin response. J Clin Endocrinol Metab 1970; 31: 24–28
- Polderman K H, Gooren L J, Asscheman H, Bakker A, Heine R J. Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 1994; 79: 265–271
- Ryan E A, Enns L. Role of gestational hormones in the induction of insulin resistance. J Clin Endocrinol Metab 1988; 67: 341–347
- Samaan N, Yen S C, Gonzalez D, Pearson O H. Metabolic effects of placental lactogen (HPL) in man. J Clin Endocrinol Metab 1968; 28: 485–491
- Catalano P M, Hoegh M, Minium J, Huston-Presley L, Bernard S, Kalhan S, Hauguel-De M S. Adiponectin in human pregnancy: Implications for regulation of glucose and lipid metabolism. Diabetologia 2006; 49: 1677–1685
- Gimeno R E, Klaman L D. Adipose tissue as an active endocrine organ: Recent advances. Curr Opin Pharmacol 2005; 5: 122–128
- Hotamisligil G S, Shargill N S, Spiegelman B M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91
- Hotamisligil G S. Inflammation and metabolic disorders. Nature 2006; 444: 860–867
- Hutley L, Prins J B. Fat as an endocrine organ: Relationship to the metabolic syndrome. Am J Med Sci 2005; 330: 280–289
- Kahn B B, Flier J S. Obesity and insulin resistance. J Clin Invest 2000; 106: 473–481
- Kahn S E, Hull R L, Utzschneider K M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840–846
- Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of metabolic syndrome X: Contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci 1999; 892: 146–154
- Montague C T, O'Rahilly S. The perils of portliness: Causes and consequences of visceral adiposity. Diabetes 2000; 49: 883–888
- Spiegelman B M, Flier J S. Obesity and the regulation of energy balance. Cell 2001; 104: 531–543
- Tilg H, Moschen A R. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–783
- Trayhurn P. Endocrine and signalling role of adipose tissue: New perspectives on fat. Acta Physiol Scand 2005; 184: 285–293
- Wellen K E, Hotamisligil G S. Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 1111–1119
- Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79–83
- Berg A H, Combs T P, Scherer P E. ACRP30/adiponectin: An adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 2002; 13: 84–89
- Hu E, Liang P, Spiegelman B M. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 1996; 271: 10 697–10 703
- Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784–1792
- Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996; 221: 286–289
- Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 2004; 24: 29–33
- Nakano Y, Tobe T, Choi-Miura N H, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem (Tokyo) 1996; 120: 803–812
- Scherer P E, Williams S, Fogliano M, Baldini G, Lodish H F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270: 26 746–26 749
- Berg A H, Scherer P E. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96: 939–949
- Campfield L A, Smith F J, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546–549
- Farooqi I S, Keogh J M, Kamath S, Jones S, Gibson W T, Trussell R, Jebb S A, Lip G Y, O'Rahilly S. Partial leptin deficiency and human adiposity. Nature 2001; 414: 34–35
- Friedman J M. Obesity in the new millennium. Nature 2000; 404: 632–634
- Halaas J L, Gajiwala K S, Maffei M, Cohen S L, Chait B T, Rabinowitz D, Lallone R L, Burley S K, Friedman J M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543–546
- Pelleymounter M A, Cullen M J, Baker M B, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540–543
- Argiles J M, Lopez-Soriano J, Busquets S, Lopez-Soriano F J. Journey from cachexia to obesity by TNF. FASEB J 1997; 11: 743–751
- Hotamisligil G S. The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med 1999; 245: 621–625
- Uysal K T, Wiesbrock S M, Marino M W, Hotamisligil G S. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389: 610–614
- Wang B, Jenkins J R, Trayhurn P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: Integrated response to TNF-alpha. Am J Physiol Endocrinol Metab 2005; 288: E731–740
- Banerjee R R, Rangwala S M, Shapiro J S, Rich A S, Rhoades B, Qi Y, Wang J, Rajala M W, Pocai A, Scherer P E, et al. Regulation of fasted blood glucose by resistin. Science 2004; 303: 1195–1198
- Holcomb I N, Kabakoff R C, Chan B, Baker T W, Gurney A, Henzel W, Nelson C, Lowman H B, Wright B D, Skelton N J, et al. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 2000; 19: 4046–4055
- Kim K H, Lee K, Moon Y S, Sul H S. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 2001; 276: 11 252–11 256
- Kusminski C M, McTernan P G, Kumar S. Role of resistin in obesity, insulin resistance and type II diabetes. Clin Sci (Lond) 2005; 109: 243–256
- Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307–312
- Despres J P, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881–887
- Rosen E D, Spiegelman B M. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444: 847–853
- Kirwan J P, Hauguel-De M S, Lepercq J, Challier J C, Huston-Presley L, Friedman J E, Kalhan S C, Catalano P M. TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes 2002; 51: 2207–2213
- Lopez-Bermejo A, Fernandez-Real J M, Garrido E, Rovira R, Brichs R, Genaro P, Bach C, Cabrero D, Kihara S, Funahashi T, et al. Maternal soluble tumour necrosis factor receptor type 2 (sTNFR2) and adiponectin are both related to blood pressure during gestation and infant's birth weight. Clin Endocrinol (Oxf) 2004; 61: 544–552
- McLachlan K A, O'Neal D, Jenkins A, Alford F P. Do adiponectin, TNFalpha, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diabetes Metab Res Rev 2006; 22: 131–138
- Retnakaran R, Hanley A J, Raif N, Connelly P W, Sermer M, Zinman B. Reduced adiponectin concentration in women with gestational diabetes: A potential factor in progression to type 2 diabetes. Diabetes Care 2004; 27: 799–800
- Silha J V, Krsek M, Skrha J V, Sucharda P, Nyomba B L, Murphy L J. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: Correlations with insulin resistance. Eur J Endocrinol 2003; 149: 331–335
- Steppan C M, Lazar M A. Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 2002; 13: 18–23
- Stumvoll M, Goldstein B J, van Haeften T W. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet 2005; 365: 1333–1346
- Farvid M S, Ng T W, Chan D C, Barrett P H, Watts G F. Association of adiponectin and resistin with adipose tissue compartments, insulin resistance and dyslipidaemia. Diabetes Obes Metab 2005; 7: 406–413
- Ahima R S, Flier J S. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11: 327–332
- Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, Giugliano D. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: A randomized trial. JAMA 2003; 289: 1799–1804
- Klok M D, Jakobsdottir S, Drent M L. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: A review. Obes Rev 2007; 8: 21–34
- Yang W S, Lee W J, Funahashi T, Tanaka S, Matsuzawa Y, Chao C L, Chen C L, Tai T Y, Chuang L M. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001; 86: 3815–3819
- Frayn K N. Obesity and metabolic disease: Is adipose tissue the culprit. Proc Nutr Soc 2005; 64: 7–13
- Gable D R, Hurel S J, Humphries S E. Adiponectin and its gene variants as risk factors for insulin resistance, the metabolic syndrome and cardiovascular disease. Atherosclerosis 2006; 188: 231–244
- Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T, et al. An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 2000; 32: 47–50
- Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 2002; 106: 2767–2770
- Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001; 103: 1057–1063
- Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H, Kumada M, Ohashi K, Okamoto Y, Nishizawa H, et al. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 2003; 42: 231–234
- Unger R H. Hyperleptinemia: Protecting the heart from lipid overload. Hypertension 2005; 45: 1031–1034
- Mazaki-Tovi S, Kanety H, Sivan E. Adiponectin and human pregnancy. Curr Diab Rep 2005; 5: 278–281
- Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Wiser A, Schiff E, Sivan E. Maternal serum adiponectin levels during human pregnancy. J Perinatol 2007; 27: 77–81
- Nien J K, Mazaki-Tovi S, Romero R, Erez O, Kusanovic J P, Gotsch F, Pineles B L, Gomez R, Edwin S, Mazor M, et al. Plasma adiponectin concentrations in non-pregnant, normal and overweight pregnant women. J Perinat Med 2007
- Sivan E, Mazaki-Tovi S, Pariente C, Efraty Y, Schiff E, Hemi R, Kanety H. Adiponectin in human cord blood: Relation to fetal birth weight and gender. J Clin Endocrinol Metab 2003; 88: 5656–5660
- Nien J K, Mazaki-Tovi S, Romero R, Kusanovic J P, Erez O, Gotsch F, Pineles B L, Friel L A, Espinoza J, Goncalves L, et al. Resistin: A hormone which induces insulin resistance is increased in normal pregnancy. J Perinat Med 2007
- Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2003; 301: 1045–1050
- Malamitsi-Puchner A, Briana D D, Boutsikou M, Kouskouni E, Hassiakos D, Gourgiotis D. Perinatal circulating visfatin levels in intrauterine growth restriction. Pediatrics 2007; 119: e1314–1318
- Sagawa N, Yura S, Itoh H, Mise H, Kakui K, Korita D, Takemura M, Nuamah M A, Ogawa Y, Masuzaki H, et al. Role of leptin in pregnancy—a review. Placenta 2002; 23(Suppl A)S80–86
- Ategbo J M, Grissa O, Yessoufou A, Hichami A, Dramane K L, Moutairou K, Miled A, Grissa A, Jerbi M, Tabka Z, et al. Modulation of adipokines and cytokines in gestational diabetes and macrosomia. J Clin Endocrinol Metab 2006; 91: 4137–4143
- Kautzky-Willer A, Pacini G, Tura A, Bieglmayer C, Schneider B, Ludvik B, Prager R, Waldhausl W. Increased plasma leptin in gestational diabetes. Diabetologia 2001; 44: 164–172
- Kinalski M, Telejko B, Kuzmicki M, Kretowski A, Kinalska I. Tumor necrosis factor alpha system and plasma adiponectin concentration in women with gestational diabetes. Horm Metab Res 2005; 37: 450–454
- Ranheim T, Haugen F, Staff A C, Braekke K, Harsem N K, Drevon C A. Adiponectin is reduced in gestational diabetes mellitus in normal weight women. Acta Obstet Gynecol Scand 2004; 83: 341–347
- Thyfault J P, Hedberg E M, Anchan R M, Thorne O P, Isler C M, Newton E R, Dohm G L, deVente J E. Gestational diabetes is associated with depressed adiponectin levels. J Soc Gynecol Investig 2005; 12: 41–45
- Williams M A, Qiu C, Muy-Rivera M, Vadachkoria S, Song T, Luthy D A. Plasma adiponectin concentrations in early pregnancy and subsequent risk of gestational diabetes mellitus. J Clin Endocrinol Metab 2004; 89: 2306–2311
- Worda C, Leipold H, Gruber C, Kautzky-Willer A, Knofler M, Bancher-Todesca D. Decreased plasma adiponectin concentrations in women with gestational diabetes mellitus. Am J Obstet Gynecol 2004; 191: 2120–2124
- Lewandowski K C, Stojanovic N, Press M, Tuck S M, Szosland K, Bienkiewicz M, Vatish M, Lewinski A, Prelevic G M, Randeva H S. Elevated serum levels of visfatin in gestational diabetes: A comparative study across various degrees of glucose tolerance. Diabetologia 2007; 50: 1033–1037
- Chan T F, Chen Y L, Lee C H, Chou F H, Wu L C, Jong S B, Tsai E M. Decreased plasma visfatin concentrations in women with gestational diabetes mellitus. J Soc Gynecol Investig 2006; 13: 364–367
- Haider D G, Handisurya A, Storka A, Vojtassakova E, Luger A, Pacini G, Tura A, Wolzt M, Kautzky-Willer A. Visfatin response to glucose is reduced in women with gestational diabetes mellitus. Diabetes Care 2007; 30: 1889–1891
- Krzyzanowska K, Krugluger W, Mittermayer F, Rahman R, Haider D, Shnawa N, Schernthaner G. Increased visfatin concentrations in women with gestational diabetes mellitus. Clin Sci (Lond) 2006; 110: 605–609
- Nien J K, Mazaki-Tovi S, Romero R, Erez O, Kusanovic J P, Gotsch F, Pineles B L, Gomez R, Edwin S, Mazor M, et al. Adiponectin in severe preeclampsia. J Perinat Med 2007
- Cortelazzi D, Corbetta S, Ronzoni S, Pelle F, Marconi A, Cozzi V, Cetin I, Cortelazzi R, Beck-Peccoz P, Spada A. Maternal and foetal resistin and adiponectin concentrations in normal and complicated pregnancies. Clin Endocrinol (Oxf) 2007; 66: 447–453
- D'Anna R, Baviera G, Corrado F, Giordano D, De V A, Nicocia G, Di B A. Adiponectin and insulin resistance in early- and late-onset pre-eclampsia. BJOG 2006; 113: 1264–1269
- Haugen F, Ranheim T, Harsem N K, Lips E, Staff A C, Drevon C A. Increased plasma levels of adipokines in preeclampsia: Relationship to placenta and adipose tissue gene expression. Am J Physiol Endocrinol Metab 2006; 290: E326–333
- Hendler I, Blackwell S C, Mehta S H, Whitty J E, Russell E, Sorokin Y, Cotton D B. The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. Am J Obstet Gynecol 2005; 193: 979–983
- Kajantie E, Kaaja R, Ylikorkala O, Andersson S, Laivuori H. Adiponectin concentrations in maternal serum: Elevated in preeclampsia but unrelated to insulin sensitivity. J Soc Gynecol Investig 2005; 12: 433–439
- Lu D, Yang X, Wu Y, Wang H, Huang H, Dong M. Serum adiponectin, leptin and soluble leptin receptor in pre-eclampsia. Int J Gynaecol Obstet 2006
- Naruse K, Yamasaki M, Umekage H, Sado T, Sakamoto Y, Morikawa H. Peripheral blood concentrations of adiponectin, an adipocyte-specific plasma protein, in normal pregnancy and preeclampsia. J Reprod Immunol 2005; 65: 65–75
- Ramsay J E, Jamieson N, Greer I A, Sattar N. Paradoxical elevation in adiponectin concentrations in women with preeclampsia. Hypertension 2003; 42: 891–894
- Tsuchida A, Yamauchi T, Ito Y, Hada Y, Maki T, Takekawa S, Kamon J, Kobayashi M, Suzuki R, Hara K, et al. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem 2004; 279: 30 817–30 822
- McCarthy J F, Misra D N, Roberts J M. Maternal plasma leptin is increased in preeclampsia and positively correlates with fetal cord concentration. Am J Obstet Gynecol 1999; 180: 731–736
- Schiff E, Friedman S A, Baumann P, Sibai B M, Romero R. Tumor necrosis factor-alpha in pregnancies associated with preeclampsia or small-for-gestational-age newborns. Am J Obstet Gynecol 1994; 170: 1224–1229
- Kershaw E E, Flier J S. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: 2548–2556
- Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner A J, Tomiyama Y, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000; 96: 1723–1732
- Berg A H, Combs T P, Du X, Brownlee M, Scherer P E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001; 7: 947–953
- Fruebis J, Tsao T S, Javorschi S, Ebbets-Reed D, Erickson M R, Yen F T, Bihain B E, Lodish H F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 2001; 98: 2005–2010
- Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, Yamauchi T, Otabe S, Okada T, Eto K, et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 2002; 51: 536–540
- Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595–1599
- Kissebah A H, Sonnenberg G E, Myklebust J, Goldstein M, Broman K, James R G, Marks J A, Krakower G R, Jacob H J, Weber J, et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci U S A 2000; 97: 14 478–14 483
- Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley R E, Tataranni P A. Hypoadiponectinemia in obesity and type 2 diabetes: Close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930–1935
- Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941–946
- Zacharova J, Chiasson J L, Laakso M. The common polymorphisms (single nucleotide polymorphism [SNP]+45 and SNP +276) of the adiponectin gene predict the conversion from impaired glucose tolerance to type 2 diabetes: The STOP-NIDDM trial. Diabetes 2005; 54: 893–899
- Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, et al. Novel modulator for endothelial adhesion molecules: Adipocyte-derived plasma protein adiponectin. Circulation 1999; 100: 2473–2476
- Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 2000; 102: 1296–1301
- Kazumi T, Kawaguchi A, Sakai K, Hirano T, Yoshino G. Young men with high-normal blood pressure have lower serum adiponectin, smaller LDL size, and higher elevated heart rate than those with optimal blood pressure. Diabetes Care 2002; 25: 971–976
- Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu Y, Motone M, Yamamoto K, Matsuo A, et al. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension 2004; 43: 1318–1323
- Matsushita K, Yatsuya H, Tamakoshi K, Wada K, Otsuka R, Takefuji S, Sugiura K, Kondo T, Murohara T, Toyoshima H. Comparison of circulating adiponectin and proinflammatory markers regarding their association with metabolic syndrome in Japanese men. Arterioscler Thromb Vasc Biol 2006; 26: 871–876
- Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 2002; 87: 2764–2769
- Despres J P, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121–2134
- Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 2004; 279: 1304–1309
- Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling. J Biol Chem 2004; 279: 28 670–28 674
- Tsao T S, Murrey H E, Hug C, Lee D H, Lodish H F. Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J Biol Chem 2002; 277: 29 359–29 362
- Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P, et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem 2003; 278: 40 352–40 363
- Aso Y, Yamamoto R, Wakabayashi S, Uchida T, Takayanagi K, Takebayashi K, Okuno T, Inoue T, Node K, Tobe T, et al. Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosorbent assay to detect HMW adiponectin. Diabetes 2006; 55: 1954–1960
- Bobbert T, Rochlitz H, Wegewitz U, Akpulat S, Mai K, Weickert M O, Mohlig M, Pfeiffer A F, Spranger J. Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes 2005; 54: 2712–2719
- Pajvani U B, Du X, Combs T P, Berg A H, Rajala M W, Schulthess T, Engel J, Brownlee M, Scherer P E. Structure–function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 2003; 278: 9073–9085
- Pajvani U B, Hawkins M, Combs T P, Rajala M W, Doebber T, Berger J P, Wagner J A, Wu M, Knopps A, Xiang A H, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 2004; 279: 12 152–12 162
- Tsao T S, Tomas E, Murrey H E, Hug C, Lee D H, Ruderman N B, Heuser J E, Lodish H F. Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways. J Biol Chem 2003; 278: 50 810–50 817
- Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, Funahashi T, Matsuzawa Y. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res 2004; 94: e27–31
- Tonelli J, Li W, Kishore P, Pajvani U B, Kwon E, Weaver C, Scherer P E, Hawkins M. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes 2004; 53: 1621–1629
- Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003; 423: 762–769
- Katsuki A, Suematsu M, Gabazza E C, Murashima S, Nakatani K, Togashi K, Yano Y, Sumida Y. Decreased high-molecular weight adiponectin-to-total adiponectin ratio in sera is associated with insulin resistance in Japanese metabolically obese, normal-weight men with normal glucose tolerance. Diabetes Care 2006; 29: 2327–2328
- Abbasi F, Chang S A, Chu J W, Ciaraldi T P, Lamendola C, McLaughlin T, Reaven G M, Reaven P D. Improvements in insulin resistance with weight loss, in contrast to rosiglitazone, are not associated with changes in plasma adiponectin or adiponectin multimeric complexes. Am J Physiol Regul Integr Comp Physiol 2006; 290: R139–144
- Basu R, Pajvani U B, Rizza R A, Scherer P E. Selective downregulation of the high molecular weight form of adiponectin in hyperinsulinemia and in type 2 diabetes: Differential regulation from nondiabetic subjects. Diabetes 2007; 56: 2174–2177
- Komaba H, Igaki N, Goto S, Yokota K, Doi H, Takemoto T, Kohno M, Hirosue Y, Goto T. Increased serum high-molecular-weight complex of adiponectin in type 2 diabetic patients with impaired renal function. Am J Nephrol 2006; 26: 476–482
- Nakashima R, Kamei N, Yamane K, Nakanishi S, Nakashima A, Kohno N. Decreased total and high molecular weight adiponectin are independent risk factors for the development of type 2 diabetes in Japanese-Americans. J Clin Endocrinol Metab 2006; 91: 3873–3877
- Araki S, Dobashi K, Kubo K, Asayama K, Shirahata A. High molecular weight, rather than total, adiponectin levels better reflect metabolic abnormalities associated with childhood obesity. J Clin Endocrinol Metab 2006; 91: 5113–5116
- Engl J, Bobbert T, Ciardi C, Laimer M, Tatarczyk T, Kaser S, Weiss H, Molnar C, Tilg H, Patsch J R, et al. Effects of pronounced weight loss on adiponectin oligomer composition and metabolic parameters. Obesity (Silver Spring) 2007; 15: 1172–1178
- Salani B, Briatore L, Andraghetti G, Adami G F, Maggi D, Cordera R. High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects. Obesity (Silver Spring) 2006; 14: 1511–1514
- Swarbrick M M, ustrheim-Smith I T, Stanhope K L, Van L, Ali M R, Wolfe B M, Havel P J. Circulating concentrations of high-molecular-weight adiponectin are increased following Roux-en-Y gastric bypass surgery. Diabetologia 2006; 49: 2552–2558
- Inoue T, Kotooka N, Morooka T, Komoda H, Uchida T, Aso Y, Inukai T, Okuno T, Node K. High molecular weight adiponectin as a predictor of long-term clinical outcome in patients with coronary artery disease. Am J Cardiol 2007; 100: 569–574
- Oki K, Koide J, Nakanishi S, Nakashima R, Yamane K. Fenofibrate increases high molecular weight adiponectin in subjects with hypertriglyceridemia. Endocr J 2007; 54: 431–435
- Aroda V, Ciaraldi T P, Chang S A, Dahan M H, Chang R J, Henry R R. Circulating and cellular adiponectin in polycystic ovary syndrome: Relationship to glucose tolerance and insulin action. Fertil Steril 2007
- Bluher M, Brennan A M, Kelesidis T, Kratzsch J, Fasshauer M, Kralisch S, Williams C J, Mantzoros C S. Total and high-molecular weight adiponectin in relation to metabolic variables at baseline and in response to an exercise treatment program: Comparative evaluation of three assays. Diabetes Care 2007; 30: 280–285
- Fisher F F, Trujillo M E, Hanif W, Barnett A H, McTernan P G, Scherer P E, Kumar S. Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia 2005; 48: 1084–1087
- Glintborg D, Frystyk J, Hojlund K, Andersen K K, Henriksen J E, Hermann A P, Hagen C, Flyvbjerg A, Andersen M. Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome. Clin Endocrinol (Oxf) 2007
- Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 2006; 29: 1357–1362
- Modan-Moses D, Stein D, Pariente C, Yaroslavsky A, Ram A, Faigin M, Loewenthal R, Yissachar E, Hemi R, Kanety H. Modulation of adiponectin and leptin during refeeding of female anorexia nervosa patients. J Clin Endocrinol Metab 2007; 92: 1843–1847
- O'Leary V B, Jorett A E, Marchetti C M, Gonzalez F, Phillips S A, Ciaraldi T P, Kirwan J P. Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin-resistant adults. Am J Physiol Endocrinol Metab 2007; 293: E421–427
- Schober F, Neumeier M, Weigert J, Wurm S, Wanninger J, Schaffler A, Dada A, Liebisch G, Schmitz G, Aslanidis C, et al. Low molecular weight adiponectin negatively correlates with the waist circumference and monocytic IL-6 release. Biochem Biophys Res Commun 2007; 361: 968–973
- Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T, Kadowaki T. Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: Comparison of activation of PPARalpha, PPARgamma, and their combination. Diabetes 2005; 54: 3358–3370
- Ong G K, Hamilton J K, Sermer M, Connelly P W, Maguire G, Zinman B, Hanley A J, Retnakaran R. Maternal serum adiponectin and infant birth weight: The role of adiponectin isoform distribution. Clin Endocrinol (Oxf) 2007; 67: 108–114
- Retnakaran R, Hanley A J, Connelly P W, Maguire G, Sermer M, Zinman B. Low serum levels of high-molecular weight adiponectin in Indo-Asian women during pregnancy: Evidence of ethnic variation in adiponectin isoform distribution. Diabetes Care 2006; 29: 1377–1379
- Takemura Y, Osuga Y, Koga K, Tajima T, Hirota Y, Hirata T, Morimoto C, Harada M, Yano T, Taketani Y. Selective increase in high molecular weight adiponectin concentration in serum of women with preeclampsia. J Reprod Immunol 2007; 73: 60–65
- Retnakaran R, Connelly P W, Maguire G, Sermer M, Zinman B, Hanley A J. Decreased high-molecular-weight adiponectin in gestational diabetes: Implications for the pathophysiology of type 2 diabetes. Diabet Med 2007; 24: 245–252
- Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser 2003; 916: i–149, backcover
- Abbasi F, Chu J W, Lamendola C, McLaughlin T, Hayden J, Reaven G M, Reaven P D. Discrimination between obesity and insulin resistance in the relationship with adiponectin. Diabetes 2004; 53: 585–590
- Kern P A, Di Gregorio G B, Lu T, Rassouli N, Ranganathan G. Adiponectin expression from human adipose tissue: Relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 2003; 52: 1779–1785
- Combs T P, Berg A H, Obici S, Scherer P E, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 2001; 108: 1875–1881
- Combs T P, Pajvani U B, Berg A H, Lin Y, Jelicks L A, Laplante M, Nawrocki A R, Rajala M W, Parlow A F, Cheeseboro L, et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 2004; 145: 367–383
- Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8: 731–737
- Nawrocki A R, Rajala M W, Tomas E, Pajvani U B, Saha A K, Trumbauer M E, Pang Z, Chen A S, Ruderman N B, Chen H, et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 2006; 281: 2654–2660
- Tomas E, Tsao T S, Saha A K, Murrey H E, Zhang C C, Itani S I, Lodish H F, Ruderman N B. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A 2002; 99: 16 309–16 313
- Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288–1295
- Chen H, Montagnani M, Funahashi T, Shimomura I, Quon M J. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 2003; 278: 45 021–45 026
- Funahashi T, Nakamura T, Shimomura I, Maeda K, Kuriyama H, Takahashi M, Arita Y, Kihara S, Matsuzawa Y. Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med 1999; 38: 202–206
- Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002; 277: 25 863–25 866
- Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 2003; 278: 2461–2468
- Chandran M, Phillips S A, Ciaraldi T, Henry R R. Adiponectin: More than just another fat cell hormone. Diabetes Care 2003; 26: 2442–2450
- Nawrocki A R, Scherer P E. The delicate balance between fat and muscle: Adipokines in metabolic disease and musculoskeletal inflammation. Curr Opin Pharmacol 2004; 4: 281–289
- Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, Nagai M, Matsuzawa Y, Funahashi T. Adiponectin as a biomarker of the metabolic syndrome. Circ J 2004; 68: 975–981
- Schulze M B, Rimm E B, Shai I, Rifai N, Hu F B. Relationship between adiponectin and glycemic control, blood lipids, and inflammatory markers in men with type 2 diabetes. Diabetes Care 2004; 27: 1680–1687
- Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N, Tagawa T, Ueda S, Shimomura I, Funahashi T, Matsuzawa Y. Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 2003; 88: 3236–3240
- Yamamoto Y, Hirose H, Saito I, Nishikai K, Saruta T. Adiponectin, an adipocyte-derived protein, predicts future insulin resistance: Two-year follow-up study in Japanese population. J Clin Endocrinol Metab 2004; 89: 87–90
- Yatagai T, Nishida Y, Nagasaka S, Nakamura T, Tokuyama K, Shindo M, Tanaka H, Ishibashi S. Relationship between exercise training-induced increase in insulin sensitivity and adiponectinemia in healthy men. Endocr J 2003; 50: 233–238
- Combs T P, Wagner J A, Berger J, Doebber T, Wang W J, Zhang B B, Tanen M, Berg A H, O'Rahilly S, Savage D B, et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: A potential mechanism of insulin sensitization. Endocrinology 2002; 143: 998–1007
- Steffes M W, Gross M D, Schreiner P J, Yu X, Hilner J E, Gingerich R, Jacobs D R, Jr. Serum adiponectin in young adults—interactions with central adiposity, circulating levels of glucose, and insulin resistance: The CARDIA study. Ann Epidemiol 2004; 14: 492–498
- Mantzoros C S, Li T, Manson J E, Meigs J B, Hu F B. Circulating adiponectin levels are associated with better glycemic control, more favorable lipid profile, and reduced inflammation in women with type 2 diabetes. J Clin Endocrinol Metab 2005; 90: 4542–4548
- Shetty G K, Economides P A, Horton E S, Mantzoros C S, Veves A. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care 2004; 27: 2450–2457
- Pischon T, Girman C J, Hotamisligil G S, Rifai N, Hu F B, Rimm E B. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004; 291: 1730–1737
- Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 2003; 23: 85–89
- Cnop M, Havel P J, Utzschneider K M, Carr D B, Sinha M K, Boyko E J, Retzlaff B M, Knopp R H, Brunzell J D, Kahn S E. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: Evidence for independent roles of age and sex. Diabetologia 2003; 46: 459–469
- Kantartzis K, Rittig K, Balletshofer B, Machann J, Schick F, Porubska K, Fritsche A, Haring H U, Stefan N. The relationships of plasma adiponectin with a favorable lipid profile, decreased inflammation, and less ectopic fat accumulation depend on adiposity. Clin Chem 2006; 52: 1934–1942
- Okada T, Saito E, Kuromori Y, Miyashita M, Iwata F, Hara M, Harada K. Relationship between serum adiponectin level and lipid composition in each lipoprotein fraction in adolescent children. Atherosclerosis 2006; 188: 179–183
- von E M, Schneider J G, Humpert P M, Kreuzer J, Kuecherer H, Katus H A, Nawroth P P, Dugi K A. Serum adiponectin levels are an independent predictor of the extent of coronary artery disease in men. J Am Coll Cardiol 2006; 47: 2124–2126
- von E M, Hamann A, Twardella D, Nawroth P P, Brenner H, Rothenbacher D. Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease. Clin Chem 2006; 52: 853–859
- Nakamura T, Kodama Y, Takano H, Umetani K, Fujioka D, Saito Y, Kawabata K, Obata J E, Kitta Y, Kobayashi T, et al. Increase in circulating levels of adiponectin after treatment with statin and fibrate in patients with coronary artery disease and hyperlipidemia. Atherosclerosis 2007; 193: 449–451
- Westphal S, Borucki K, Taneva E, Makarova R, Luley C. Adipokines and treatment with niacin. Metabolism 2006; 55: 1283–1285
- Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, et al. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 2002; 105: 2893–2898
- Matsuzawa Y, Shimomura I, Kihara S, Funahashi T. Importance of adipocytokines in obesity-related diseases. Horm Res 2003; 60(Suppl 3)56–59
- Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005; 26: 439–451
- Koerner A, Kratzsch J, Kiess W. Adipocytokines: Leptin – the classical, resistin – the controversial, adiponectin – the promising, and more to come. Best Pract Res Clin Endocrinol Metab 2005; 19: 525–546
- Ouchi N, Shibata R, Walsh K. Cardioprotection by adiponectin. Trends Cardiovasc Med 2006; 16: 141–146
- Scherer P E. Adipose tissue: From lipid storage compartment to endocrine organ. Diabetes 2006; 55: 1537–1545
- Bora P S, Kaliappan S, Lyzogubov V V, Tytarenko R G, Thotakura S, Viswanathan T, Bora N S. Expression of adiponectin in choroidal tissue and inhibition of laser induced choroidal neovascularization by adiponectin. FEBS Lett 2007; 581: 1977–1982
- Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T, Cao Y. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 2004; 101: 2476–2481
- Vona-Davis L, Howard-McNatt M, Rose D P. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes Rev 2007; 8: 395–408
- Butte N F, Wong W W, Treuth M S, Ellis K J, O'Brian S E. Energy requirements during pregnancy based on total energy expenditure and energy deposition. Am J Clin Nutr 2004; 79: 1078–1087
- Catalano P M. Management of obesity in pregnancy. Obstet Gynecol 2007; 109: 419–433
- Ehrenberg H M, Huston-Presley L, Catalano P M. The influence of obesity and gestational diabetes mellitus on accretion and the distribution of adipose tissue in pregnancy. Am J Obstet Gynecol 2003; 189: 944–948
- Hytten F E, Chamberlain G. Clinical physiology in obstetrics. Blackwell Scientifc Publications, OxfordUnited Kingdom 1991
- Kinoshita T, Itoh M. Longitudinal variance of fat mass deposition during pregnancy evaluated by ultrasonography: The ratio of visceral fat to subcutaneous fat in the abdomen. Gynecol Obstet Invest 2006; 61: 115–118
- Pipe N G, Smith T, Halliday D, Edmonds C J, Williams C, Coltart T M. Changes in fat, fat-free mass and body water in human normal pregnancy. Br J Obstet Gynaecol 1979; 86: 929–940
- Aberg A, Rydhstroem H, Frid A. Impaired glucose tolerance associated with adverse pregnancy outcome: A population-based study in southern Sweden. Am J Obstet Gynecol 2001; 184: 77–83
- Al-Shawaf T, Moghraby S, Akiel A. Does impaired glucose tolerance imply a risk in pregnancy. Br J Obstet Gynaecol 1988; 95: 1036–1041
- Dixon J B, Dixon M E, O'Brien P E. Birth outcomes in obese women after laparoscopic adjustable gastric banding. Obstet Gynecol 2005; 106: 965–972
- Weiss J L, Malone F D, Emig D, Ball R H, Nyberg D A, Comstock C H, Saade G, Eddleman K, Carter S M, Craigo S D, et al. Obesity, obstetric complications and cesarean delivery rate—a population-based screening study. Am J Obstet Gynecol 2004; 190: 1091–1097
- Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk factors for preeclampsia. JAMA 1991; 266: 237–241
- Joffe G M, Esterlitz J R, Levine R J, Clemens J D, Ewell M G, Sibai B M, Catalano P M. The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Calcium for Preeclampsia Prevention (CPEP) study group. Am J Obstet Gynecol 1998; 179: 1032–1037
- Sibai B M, Gordon T, Thom E, Caritis S N, Klebanoff M, McNellis D, Paul R H. Risk factors for preeclampsia in healthy nulliparous women: A prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal–Fetal Medicine Units. Am J Obstet Gynecol 1995; 172: 642–648
- Solomon C G, Seely E W. Hypertension in pregnancy: A manifestation of the insulin resistance syndrome. Hypertension 2001; 37: 232–239
- Wolf M, Sandler L, Munoz K, Hsu K, Ecker J L, Thadhani R. First trimester insulin resistance and subsequent preeclampsia: A prospective study. J Clin Endocrinol Metab 2002; 87: 1563–1568
- Crowther C A, Hiller J E, Moss J R, McPhee A J, Jeffries W S, Robinson J S. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352: 2477–2486
- Yogev Y, Xenakis E M, Langer O. The association between preeclampsia and the severity of gestational diabetes: The impact of glycemic control. Am J Obstet Gynecol 2004; 191: 1655–1660
- D'Anna R, Baviera G, Corrado F, Giordano D, Di Benedetto A, Jasonni V M. Plasma adiponectin concentration in early pregnancy and subsequent risk of hypertensive disorders. Obstet Gynecol 2005; 106: 340–344
- Suwaki N, Masuyama H, Nakatsukasa H, Masumoto A, Sumida Y, Takamoto N, Hiramatsu Y. Hypoadiponectinemia and circulating angiogenic factors in overweight patients complicated with pre-eclampsia. Am J Obstet Gynecol 2006
- Crouch E, Persson A, Chang D, Heuser J. Molecular structure of pulmonary surfactant protein D (SP-D). J Biol Chem 1994; 269: 17 311–17 319
- McCormack F X, Pattanajitvilai S, Stewart J, Possmayer F, Inchley K, Voelker D R. The Cys6 intermolecular disulfide bond and the collagen-like region of rat SP-A play critical roles in interactions with alveolar type II cells and surfactant lipids. J Biol Chem 1997; 272: 27 971–27 979
- Wong G W, Wang J, Hug C, Tsao T S, Lodish H F. A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci U S A 2004; 101: 10 302–10 307
- Wang Y, Xu A, Knight C, Xu L Y, Cooper G J. Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity. J Biol Chem 2002; 277: 19 521–19 529
- Wang Y, Lam K S, Chan L, Chan K W, Lam J B, Lam M C, Hoo R C, Mak W W, Cooper G J, Xu A. Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem 2006; 281: 16 391–16 400
- Phillips S A, Ciaraldi T P, Kong A P, Bandukwala R, Aroda V, Carter L, Baxi S, Mudaliar S R, Henry R R. Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy. Diabetes 2003; 52: 667–674
- Abke S, Neumeier M, Weigert J, Wehrwein G, Eggenhofer E, Schaffler A, Maier K, Aslanidis C, Scholmerich J, Buechler C. Adiponectin-induced secretion of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8) is impaired in monocytes from patients with type I diabetes. Cardiovasc Diabetol 2006; 5: 17
- Rovin B H, Song H. Chemokine induction by the adipocyte-derived cytokine adiponectin. Clin Immunol 2006; 120: 99–105
- Haugen F, Drevon C A. Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. Endocrinology 2007; 148: 5478–5486
- Neumeier M, Weigert J, Schaffler A, Wehrwein G, Muller-Ladner U, Scholmerich J, Wrede C, Buechler C. Different effects of adiponectin isoforms in human monocytic cells. J Leukoc Biol 2006; 79: 803–808
- Tasanen K, Eble J A, Aumailley M, Schumann H, Baetge J, Tu H, Bruckner P, Bruckner-Tuderman L. Collagen XVII is destabilized by a glycine substitution mutation in the cell adhesion domain Col15. J Biol Chem 2000; 275: 3093–3099
- Lara-Castro C, Luo N, Wallace P, Klein R L, Garvey W T. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 2006; 55: 249–259
- Wang A Y, Hickman I J, Richards A A, Whitehead J P, Prins J B, Macdonald G A. High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3, but not genotype 1 infection. Am J Gastroenterol 2005; 100: 2717–2723
- Iwahashi H, Funahashi T, Kurokawa N, Sayama K, Fukuda E, Okita K, Imagawa A, Yamagata K, Shimomura I, Miyagawa J I, et al. Plasma adiponectin levels in women with anorexia nervosa. Horm Metab Res 2003; 35: 537–540
- Ebinuma H, Miyazaki O, Yago H, Hara K, Yamauchi T, Kadowaki T. A novel ELISA system for selective measurement of human adiponectin multimers by using proteases. Clin Chim Acta 2006; 372: 47–53
- Ebinuma H, Miida T, Yamauchi T, Hada Y, Hara K, Kubota N, Kadowaki T. Improved ELISA for selective measurement of adiponectin multimers and identification of adiponectin in human cerebrospinal fluid. Clin Chem 2007; 53: 1541–1544
- Nakano Y, Tajima S, Yoshimi A, Akiyama H, Tsushima M, Tanioka T, Negoro T, Tomita M, Tobe T. A novel enzyme-linked immunosorbent assay specific for high-molecular-weight adiponectin. J Lipid Res 2006; 47: 1572–1582
- Hammarstedt A, Sopasakis V R, Gogg S, Jansson P A, Smith U. Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects. Diabetologia 2005; 48: 96–104
- Fuglsang J, Skjaerbaek C, Frystyk J, Flyvbjerg A, Ovesen P. A longitudinal study of serum adiponectin during normal pregnancy. BJOG 2006; 113: 110–113
- Catalano P M, Nizielski S E, Shao J, Preston L, Qiao L, Friedman J E. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: Relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab 2002; 282: E522–533
- Desoye G, Schweditsch M O, Pfeiffer K P, Zechner R, Kostner G M. Correlation of hormones with lipid and lipoprotein levels during normal pregnancy and postpartum. J Clin Endocrinol Metab 1987; 64: 704–712
- Paradisi G, Biaggi A, Ferrazzani S, De C S, Caruso A. Abnormal carbohydrate metabolism during pregnancy: Association with endothelial dysfunction. Diabetes Care 2002; 25: 560–564
- Sivan E, Homko C J, Chen X, Reece E A, Boden G. Effect of insulin on fat metabolism during and after normal pregnancy. Diabetes 1999; 48: 834–838
- Faust I M, Johnson P R, Stern J S, Hirsch J. Diet-induced adipocyte number increase in adult rats: A new model of obesity. Am J Physiol 1978; 235: E279–286
- Garaulet M, Hernandez-Morante J J, Lujan J, Tebar F J, Zamora S. Relationship between fat cell size and number and fatty acid composition in adipose tissue from different fat depots in overweight/obese humans. Int J Obes (Lond) 2006; 30: 899–905
- Hausman D B, DiGirolamo M, Bartness T J, Hausman G J, Martin R J. The biology of white adipocyte proliferation. Obes Rev 2001; 2: 239–254
- Hirsch J, Batchelor B. Adipose tissue cellularity in human obesity. Clin Endocrinol Metab 1976; 5: 299–311
- Johnson P R, Stern J S, Greenwood M R, Hirsch J. Adipose tissue hyperplasia and hyperinsulinemia on Zucker obese female rats: A developmental study. Metabolism 1978; 27: 1941–1954
- Prins J B, O'Rahilly S. Regulation of adipose cell number in man. Clin Sci (Lond) 1997; 92: 3–11
- Tontonoz P, Hu E, Spiegelman B M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994; 79: 1147–1156
- Yu J G, Javorschi S, Hevener A L, Kruszynska Y T, Norman R A, Sinha M, Olefsky J M. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002; 51: 2968–2974
- He W, Barak Y, Hevener A, Olson P, Liao D, Le J, Nelson M, Ong E, Olefsky J M, Evans R M. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A 2003; 100: 15 712–15 717
- Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003; 52: 1655–1663
- Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide T, Kubota N, Terauchi Y, Tobe K, et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 2001; 276: 41 245–41 254
- Yang W S, Jeng C Y, Wu T J, Tanaka S, Funahashi T, Matsuzawa Y, Wang J P, Chen C L, Tai T Y, Chuang L M. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 2002; 25: 376–380
- de Souza C J, Eckhardt M, Gagen K, Dong M, Chen W, Laurent D, Burkey B F. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 2001; 50: 1863–1871
- De V P, Lefebvre A M, Miller S G, Guerre-Millo M, Wong K, Saladin R, Hamann L G, Staels B, Briggs M R, Auwerx J. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest 1996; 98: 1004–1009
- Hulver M W, Zheng D, Tanner C J, Houmard J A, Kraus W E, Slentz C A, Sinha M K, Pories W J, MacDonald K G, Dohm G L. Adiponectin is not altered with exercise training despite enhanced insulin action. Am J Physiol Endocrinol Metab 2002; 283: E861–865
- Kopp H P, Krzyzanowska K, Mohlig M, Spranger J, Pfeiffer A F, Schernthaner G. Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women. Int J Obes (Lond) 2005; 29: 766–771
- Faraj M, Havel P J, Phelis S, Blank D, Sniderman A D, Cianflone K. Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 2003; 88: 1594–1602
- Pender C, Goldfine I D, Tanner C J, Pories W J, MacDonald K G, Havel P J, Houmard J A, Youngren J F. Muscle insulin receptor concentrations in obese patients post bariatric surgery: Relationship to hyperinsulinemia. Int J Obes Relat Metab Disord 2004; 28: 363–369
- Polak J, Kovacova Z, Jacek M, Klimcakova E, Kovacikova M, Vitkova M, Kuda O, Sebela M, Samcova E, Stich V. An increase in plasma adiponectin multimeric complexes follows hypocaloric diet-induced weight loss in obese and overweight pre-menopausal women. Clin Sci (Lond) 2007; 112: 557–565
- Delporte M L, Brichard S M, Hermans M P, Beguin C, Lambert M. Hyperadiponectinaemia in anorexia nervosa. Clin Endocrinol (Oxf) 2003; 58: 22–29
- Pannacciulli N, Vettor R, Milan G, Granzotto M, Catucci A, Federspil G, De G P, Giorgino R, De P G. Anorexia nervosa is characterized by increased adiponectin plasma levels and reduced nonoxidative glucose metabolism. J Clin Endocrinol Metab 2003; 88: 1748–1752