Alternative titles; symbols
HGNC Approved Gene Symbol: ADIPOQ
Cytogenetic location: 3q27.3 Genomic coordinates (GRCh38): 3:186,842,710-186,858,463 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q27.3 | Adiponectin deficiency | 612556 | Autosomal dominant | 3 |
Adiponectin is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. Adipocytes also produce and secrete proteins such as leptin (LEP; 164160), adipsin (factor D; 134350), various other complement components (e.g., properdin (see 138470) and C3a (see 120700)), and tumor necrosis factor (TNF; 191160), suggesting a possible link to the immune system. Adiponectin, an adipose tissue-specific plasma protein, has antiinflammatory effects on the cellular components of the vascular wall (summary by Ouchi et al., 1999; Ouchi et al., 2000).
By constructing and screening an adipose tissue cDNA library for novel genes, Maeda et al. (1996) isolated a cDNA encoding APM1, an adipose tissue-specific collagen-like factor. Sequence analysis predicted that the 244-amino acid secretory protein has a signal peptide but no transmembrane hydrophobic stretch, and a short N-terminal noncollagenous sequence followed by a short collagen-like motif of G-X-Y repeats. APM1 shares significant similarity to collagen X (see 120110), collagen VIII (see 120252), and complement protein C1q (see 120550) within the C terminus. Northern blot analysis detected a 4.5-kb APM1 transcript in adipose tissue but not in muscle, intestine, placenta, uterus, ovary, kidney, liver, lung, brain, or heart.
Saito et al. (1999) cloned an adipose tissue-specific gene they termed GBP28. They stated that the GBP28 protein is encoded by the APM1 mRNA identified by Maeda et al. (1996).
By genomic sequence analysis, Saito et al. (1999) and Schaffler et al. (1999) determined that the GBP28 gene spans 16 kb and contains 3 exons, and that the promoter lacks a TATA box. By Southern blot and genomic sequence analyses, Das et al. (2001) determined that the mouse gene, which they termed Acrp30 (adipocyte complement-related protein, 30-kD), contains 3 exons and spans 20 kb.
Using FISH, Saito et al. (1999) mapped the APM1 gene to chromosome 3q27. However, also by FISH, Schaffler et al. (1999) mapped the APM1 gene to 1q21.3-q23. By radiation hybrid analysis, Takahashi et al. (2000) confirmed that the APM1 gene maps to 3q27. Using FISH, Das et al. (2001) mapped the mouse Acrp30 gene to chromosome 16 in a region showing homology of synteny with human 3q27.
By RNase protection and Western blot analysis, Schaffler et al. (1999) showed that APM1 is expressed by differentiated adipocytes as a 33-kD protein that is also detectable in serum. By sequence comparisons, they found links between APM1 and TNF family ligands as well as to cytokines expressed by T cells.
Using cell ELISA analysis, Ouchi et al. (1999) determined that the APM1 gene product, which they termed adiponectin, suppressed TNF-induced monocyte adhesion to aortic endothelial cells (HAECs), as well as expression of vascular cell adhesion molecule-1 (VCAM1; 192225), selectin E (SELE; 131210), and intercellular adhesion molecule-1 (ICAM1; 147840) on HAECs, in a dose-dependent manner. These results indicated that adiponectin may attenuate the inflammatory response associated with atherogenesis. In addition, Ouchi et al. (1999) found that plasma adiponectin values were significantly lower in patients with coronary artery disease compared with those of subjects matched for age and body mass index. By immunoblot analysis, Ouchi et al. (2000) extended these studies to show that adiponectin suppresses TNF-induced I-kappa-B-alpha (IKBA; 164008) phosphorylation and nuclear factor kappa-B (NFKB; see 164011) activation without affecting the interaction of TNF and its receptors or other TNF-mediated phosphorylation signals. The inhibitory effect was accompanied by cAMP accumulation, which could be blocked by adenylate cyclase or protein kinase A (PKA; see 176911) inhibitors. These results, together with a finding by Arita et al. (1999) that plasma adiponectin values are low in obese subjects, suggested that adiponectin levels may be helpful in assessing the risk for coronary artery disease.
Using hematopoietic colony formation assays, Yokota et al. (2000) showed that adiponectin inhibited myelomonocytic progenitor cell proliferation, at least in part due to apoptotic mechanisms, at physiologic concentrations of the protein (approximately 2.0 to 17 micrograms/ml in plasma). Analysis of colony formation from CD34 (142230)-positive stem cells in the presence of a combination of growth factors showed that CFU-GM (myelomonocytic) but not BFU-E (erythrocytic) colony formation was inhibited by adiponectin and by complement factor C1q. Proliferation of lymphoid cell lines was not inhibited by adiponectin. Northern blot analysis revealed that adiponectin-treated cells had reduced expression of the antiapoptotic BCL2 gene (151430) but not of apoptosis-inducing factors such as BAX (600040). Analysis of macrophage function established that adiponectin suppresses phagocytic activity as well as lipopolysaccharide (LPS)-induced TNF, but not interleukin-1B (IL1B; 147720) or interleukin-6 (IL6; 147620), production and expression. Blockade of C1QRP (120577), a C1q receptor on macrophages, abrogated the suppression of phagocytic function but not the inhibition of TNF production or myelomonocytic cell proliferation mediated by adiponectin. Yokota et al. (2000) suggested that adiponectin is an important regulator of hematopoiesis and inflammatory responses that acts through C1QRP and other receptors.
Yamauchi et al. (2002) demonstrated that phosphorylation and activation of the 5-prime-AMP-activated protein kinase (AMPK; see 602739) are stimulated with globular and full-length adiponectin in skeletal muscle and only with full-length adiponectin in the liver. In parallel with its activation of AMPK, adiponectin stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC1; 200350), fatty acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by a dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty acid oxidation by adiponectin occurs through activation of AMPK. Yamauchi et al. (2002) concluded that their data provided a novel paradigm, that an adipocyte-derived antidiabetic hormone, adiponectin, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
Yokota et al. (2002) found that brown fat in normal human bone marrow contains adiponectin and used marrow-derived preadipocyte lines and long-term cultures to explore potential roles of adiponectin in hematopoiesis. Recombinant adiponectin blocked fat cell formation in long-term bone marrow cultures and inhibited the differentiation of cloned stromal preadipocytes. Adiponectin also caused elevated expression of COX2 (600262) by these stromal cells and induced release of prostaglandin E2. A COX2 inhibitor prevented the inhibitory action of adiponectin on preadipocyte differentiation, suggesting involvement of stromal cell-derived prostanoids. Furthermore, adiponectin failed to block fat cell generation when bone marrow cells were derived from COX2 heterozygous mice. Yokota et al. (2002) concluded that preadipocytes represent direct targets for adiponectin action, establishing a paracrine negative feedback loop for fat regulation. They also linked adiponectin to the COX2-dependent prostaglandins that are critical in this process.
Using SDS-PAGE to analyze human and mouse adiponectin from serum or adipocytes and recombinant adiponectin expressed in mammalian cells, Waki et al. (2003) detected 3 different molecular mass species and characterized them as low-molecular weight (LMW) trimers (67 kD), middle-molecular weight (MMW) hexamers (136 kD), and high-molecular weight 12- to 18-mers (greater than 300 kD). A disulfide bond through an N-terminal cysteine was required for the formation of multimers larger than a trimer. Noting that Arita et al. (1999) had found total adiponectin concentrations to be higher in females than in males, Waki et al. (2003) analyzed serum samples from healthy young Japanese volunteers and found that HMW multimers, but not MMW or LMW multimers, were significantly less abundant in males than females.
Sivan et al. (2003) sought to determine if adiponectin is present in human fetal blood, to define its association with fetal birth weight, and to evaluate whether dynamic changes in adiponectin levels occur during the early neonatal period. Cord blood adiponectin levels were extremely high compared with serum levels in children and adults and were positively correlated with fetal birth weights. No significant differences in adiponectin levels were found between female and male neonates. Cord adiponectin levels were significantly higher compared with maternal levels at birth, and no correlation was found between cord and maternal adiponectin levels. Sivan et al. (2003) concluded that adiponectin in cord blood is derived from fetal and not from placental or maternal tissues.
Kumada et al. (2004) incubated human monocyte-derived macrophages with physiologic concentrations of recombinant human adiponectin to determine the effect of adiponectin on matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Adiponectin treatment increased TIMP1 (305370) mRNA levels in a dose-dependent manner without affecting MMP9 (120361) mRNA. Adiponectin also augmented TIMP1 secretion into the media. Adiponectin significantly increased IL10 (124092) mRNA expression and protein secretion. Cotreatment of cells with adiponectin and anti-IL10 monoclonal antibodies abolished adiponectin-induced TIMP1 mRNA expression. Kumada et al. (2004) concluded that adiponectin acts as an antiinflammatory signal by selectively increasing TIMP1 expression through IL10 induction.
Biochemical, genetic, and animal studies established a critical role for Acrp30/adiponectin in controlling whole-body metabolism, particularly by enhancing insulin sensitivity in muscle and liver, and by increasing fatty acid oxidation in muscle. Wong et al. (2004) described a widely expressed and highly conserved family of adiponectin paralogs. They focused particularly on the mouse paralog most similar to adiponectin, CTRP2. At nanomolar concentrations, bacterially produced CTRP2 rapidly induced phosphorylation of AMP-activated protein kinase (see 600497), acetyl-coA carboxylase (see 200350), and mitogen-activated protein kinase (see 176872) in cultured myotubes, which resulted in increased glycogen accumulation and fatty acid oxidation. The authors suggested that the discovery of the family of adiponectin paralogs has implications for understanding the control of energy homeostasis and could provide new targets for pharmacologic intervention in metabolic diseases such as diabetes and obesity.
To study how the biologic activities of adiponectin are transmitted, Hug et al. (2004) performed a series of expression cloning studies to identify cell surface molecules capable of binding adiponectin, using a magnetic-bead panning method that may present higher-valency forms of the adiponectin ligand. Specifically, they transduced a C2C12 myoblast cDNA retroviral expression library into Ba/F3 cells and panned infected cells on recombinant adiponectin linked to magnetic beads. They identified T-cadherin (see 601364) as a receptor for the hexameric and high molecular weight species of adiponectin but not for the trimeric or globular species. Only eukaryotically expressed adiponectin bound to T-cadherin, implying that posttranslational modifications of adiponectin are critical for binding. T-cadherin is expressed in endothelial and smooth muscle cells, where it is positioned to interact with adiponectin. Because T-cadherin is a glycosylphosphatidylinositol-anchored extracellular protein, it may act as a coreceptor for a signaling receptor through which adiponectin transmits metabolic signals.
Iwabu et al. (2010) provided evidence that adiponectin induces extracellular calcium influx by adiponectin receptor-1 (ADIPOR1; 607945), which was necessary for subsequent activation of calcium/calmodulin-dependent protein kinase kinase-beta (CaMKK-beta; CAMKK2), AMPK (600497), and SIRT1 (604479), increased expression and decreased acetylation of PGC1-alpha (604517), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular calcium concentration, and decreased the activation of CaMkk, AMPK, and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC1-alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibers, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance.
Role in Disease
Yang et al. (2001) studied the changes of plasma adiponectin levels with body weight reduction among 22 obese patients who received gastric partition surgery. A 46% increase of mean plasma adiponectin level was accompanied by a 21% reduction in mean BMI. The authors concluded that body weight reduction increased the plasma levels of a protective adipocytokine, adiponectin. In addition, they inferred that the increase in plasma adiponectin despite the reduction of the only tissue of its own synthesis suggests that the expression of adiponectin is under feedback inhibition in obesity.
Lindsay et al. (2002) found that 70 Pima Indian patients who later developed type 2 diabetes (see 125853) had, at baseline, lower concentrations of adiponectin than did controls. Those individuals with high concentrations of the protein were less likely to develop type 2 diabetes than those with low concentrations.
Stefan et al. (2002) measured fasting plasma adiponectin and insulin concentrations and body composition in 30 5-year-old and 53 10-year-old Pima Indian children. Cross-sectionally, plasma adiponectin concentrations were negatively correlated with percentage body fat and fasting plasma insulin concentrations at both 5 and 10 years of age. At age 10 years, percentage body fat (p = 0.03), but not fasting plasma insulin, was independently associated with fasting plasma adiponectin concentrations. Longitudinally, plasma adiponectin concentrations decreased with increasing adiposity. Longitudinal analyses indicated that hypoadiponectinemia is a consequence of the development of obesity in childhood.
Tagami et al. (2004) studied adiponectin levels in 31 female patients with anorexia nervosa and in 11 with bulimia nervosa. Serum adiponectin concentrations in anorexia nervosa and bulimia nervosa were significantly lower than those in normal-weight controls. These results were unexpected in light of reports that circulating adiponectin levels are downregulated in obesity (Arita et al., 1999) and that weight reduction increases plasma adiponectin levels (Yang et al., 2001); levels were high in constitutionally thin subjects and low in obese subjects, which provided a negative correlation with body mass index (BMI) and body fat mass. In contrast, serum leptin (164160) levels correlated very well with BMI and fat mass among all the patients and controls. The concentrations of adiponectin after weight recovery increased to the normal level despite a relatively small increase in BMI. The authors suggested that abnormal feeding behavior in patients with eating disorders may reduce circulating adiponectin levels, and that weight recovery can restore it.
Williams et al. (2004) determined the extent to which low maternal plasma adiponectin is predictive of gestational diabetes mellitus (GDM), a condition that is biochemically and epidemiologically similar to type 2 diabetes, using a prospective, nested case-control study design to compare maternal plasma adiponectin concentrations in 41 cases with 70 controls. Adiponectin concentrations were statistically significantly lower in women with GDM than controls (4.4 vs 8.1 microg/ml, P less than 0.001). Approximately 73% of women with GDM, compared with 33% of controls, had adiponectin concentrations less than 6.4 microg/ml. After adjusting for confounding, women with adiponectin concentrations less than 6.4 microg/ml experienced a 4.6-fold increased risk of GDM, as compared with those with higher concentrations (95% confidence interval, 1.8-11.6). The authors concluded that their findings were consistent with other reports suggesting an association between hypoadiponectinemia and risk of type 2 diabetes.
Using Spearman univariate analysis, Liu et al. (2007) demonstrated that both total and high molecular weight adiponectin levels were inversely associated with body mass index (BMI), fasting glucose, homeostasis model of assessment of insulin resistance, triglycerides, and alanine aminotransferase (ALT), with the high molecular weight isoform also positively correlated with high-density lipoprotein cholesterol (r = 0.19; p = 0.036). They concluded that high molecular weight adiponectin, but not hexameric or trimeric, tracks with the metabolic correlates of total adiponectin and that an independent inverse association exists between ALT and high molecular weight adiponectin.
Adiponectin Deficiency
By direct sequencing and restriction fragment polymorphism analysis, Takahashi et al. (2000) identified 2 nucleotide changes in the adiponectin gene in 219 Japanese subjects. A conservative G-to-T substitution at nucleotide 94 of exon 2 was associated with higher but not statistically significant plasma adiponectin values. The allelic frequency of T (71%) was not different between the 142 nonobese and 77 obese subjects. One nonobese man with coronary artery disease, lung thrombosis, and autoimmune disease had an R112C mutation (605441.0001) and a markedly low concentration (1.16 microg/ml) of plasma adiponectin. Only 1 of his 4 children carried the mutation and had a low concentration of plasma adiponectin.
Waki et al. (2003) analyzed 8 previously reported mutations in the ADIPOQ gene and found that G84R and G90S mutants, associated with diabetes and hypoadiponectinemia (Vasseur et al., 2002), did not form HMW multimers. R112C (605441.0001) and I164T mutants, associated with hypoadiponectinemia, did not assemble into LMW trimers, resulting in impaired secretion from the cell. The authors suggested that impaired multimerization and/or the consequent impaired secretion may underlie the diabetic phenotype and hypoadiponectinemia associated with these mutations, and that multimer distribution as well as total concentration should be considered in the interpretation of plasma adiponectin levels.
Simeone et al. (2022) used unified linkage analysis and rare variant association testing on 6 family members with type 2 diabetes mellitus, end-stage renal disease (ESRD), and markedly decreased adiponectin levels and 524 ethnically matched background controls. They identified a heterozygous 10-bp deletion in exon 3 of the ADIPOQ gene (605441.0002) in all 6 family members. Sanger sequencing confirmation of the ADIPOQ variant was performed in all 6 individuals as well as in 8 additional family members for whom DNA was available. Four of the additional family members carried the deletion, 2 who had diabetes only and 2 who were unaffected. The deletion was seen only once among 56,810 exome and genome sequences from non-Finnish Europeans reported in gnomAD.
Association Studies
Comuzzie et al. (2001) assayed serum levels of adiponectin in 1,100 adults of predominantly northern European ancestry distributed across 170 families. Quantitative genetic analysis of adiponectin levels detected an additive genetic heritability of 46%. They identified 2 quantitative trait loci influencing adiponectin expression: one on chromosome 5 (ADIPQTL2; 606770), and the other on chromosome 14 (ADIPQTL3; 606771). The detection of a significant linkage with a quantitative trait locus on chromosome 5 provided strong evidence for a replication of a previously reported quantitative trait locus for obesity-related phenotypes.
Mackevics et al. (2006) investigated the association of 2 SNPs of the ACDC gene, 45T-G (rs2241766) and 276G-T, and their haplotypes with serum adiponectin concentrations, metabolic parameters and intima-media thickness of the carotid arteries in 1,745 well-phenotyped, asymptomatic, unrelated Caucasian Austrian individuals. Mackevics et al. (2006) replicated a strong association of ACDC 45T-G/276G-T genotypes and haplotypes with adiponectin levels that was previously reported by Menzaghi et al. (2002), but found no significant association with the majority of metabolic parameters of the insulin resistance syndrome (605552) or carotid intima-media thickness.
In 252 young Finnish men, Mousavinasab et al. (2006) analyzed the association of the 45T-G and 276G-T SNPs with serum adiponectin level and insulin resistance-associated risk factors and found that serum adiponectin level and diastolic blood pressure were significantly higher with the 276TT genotype compared to 276GT and 276GG genotypes (p less than 0.001 and p = 0.031, respectively). After adjustment for other covariates, the interaction between triglycerides and the 276G-T SNP remained statistically significant (p = 0.009); among individuals with the 276TT genotype, an increase in triglyceride level was associated with a decrease in serum adiponectin concentration. Mousavinasab et al. (2006) noted that it is possible that the 2 polymorphisms are in linkage disequilibrium with other loci that may be responsible for the observed associations.
Maeda et al. (2002) generated mice deficient in adiponectin/ACRP30 by targeted disruption. Homozygous mutant mice showed delayed clearance of free fatty acid in plasma, low levels of fatty acid transport protein-1 (FATP1; 600691) mRNA in muscle, high levels of TNF-alpha (191160) mRNA in adipose tissue, and high plasma TNF-alpha concentrations. The knockout mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate-1 (IRS1; 147545)-associated phosphatidylinositol 3-kinase (PI3K; see 171833) activity in muscle. Viral-mediated adiponectin/ACRP30 expression in knockout mice reversed the reduction of FATP1 mRNA, the increase of adipose TNF-alpha mRNA, and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP1 mRNA, IRS1-associated PI3K activity, and glucose uptake, whereas adiponectin increased these parameters. Maeda et al. (2002) concluded that adiponectin/ACRP30 deficiency and high TNFA-alpha levels in knockout mice reduced muscle FATP1 mRNA and IRS1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.
Yamauchi et al. (2003) crossed mice carrying a transgene for the globular domain of adiponectin with leptin-deficient ob/ob mice or with apoE (107741)-deficient mice. Ob/ob mice carrying the transgene showed reduced insulin resistance, beta-cell degranulation, and diabetes. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation, such as acyl-CoA oxidase (ACOX1; 609751), and molecules involved in energy dissipation, such as uncoupling protein-2 (601693) and -3 (602044). When expressed on the ApoE-deficient background, the globular domain of adiponectin showed reduced atherosclerosis, even though plasma glucose and lipid levels remained the same. The protection from atherosclerosis was associated with decreased expression of class A scavenger receptor (see 153622) and TNFA.
Matsuda et al. (2002) found that adiponectin-deficient mice showed severe neointimal thickening and increased proliferation of vascular smooth muscle cells in a mechanical injury model of restenotic change following balloon angioplasty. Adenovirus-mediated supplement of adiponectin attenuated neointimal proliferation. In cultured smooth muscle cells, adiponectin attenuated DNA synthesis induced by platelet-derived growth factor (PDGFB; 190040), heparin-binding EGF-like growth factor (HBEGF; 126150), and basic fibroblast growth factor (FGF2; 134920). Adiponectin supplementation also attenuated the smooth muscle cell proliferation and migration induced by HBEGF. In cultured endothelial cells, adiponectin attenuated HBEGF expression stimulated by TNF-alpha. Matsuda et al. (2002) concluded that a therapeutic strategy to increase plasma adiponectin should be useful in preventing vascular restenosis after angioplasty.
Qi et al. (2004) demonstrated that adiponectin acts in the brain to decrease body weight. They detected a rise in adiponectin in cerebrospinal fluid after intravenous injection, consistent with brain transport. In contrast to leptin (164160), intracerebroventricular administration of adiponectin decreased body weight mainly by stimulating energy expenditure. Full-length adiponectin, mutant adiponectin with cysteine-39 replaced with serine, and globular adiponectin were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to intracerebroventricular injection and systemic adiponectin, which resulted in increased thermogenesis, weight loss, and reduction in serum glucose and lipid levels. Adiponectin also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH; 122560), adiponectin had no substantial effect on other neuropeptide targets of leptin. Agouti mice (see 600201) did not respond to adiponectin or leptin, indicating the melanocortin pathway may be a common target.
Shklyaev et al. (2003) generated a series of recombinant adeno-associated virus vectors of serotypes 1 and 5 encoding mouse Acrp30 cDNAs. The long-term expression of recombinant vectors was tested after intramuscular or intraportal injection in female Sprague-Dawley rats with diet-induced obesity. A single peripheral injection of 10(12) physical particles of Acrp30-encoding vectors resulted in sustained (up to 280 days) significant reduction in body weight, concomitant with the reduction in daily food intake. Acrp30 treatment resulted in a higher peripheral insulin sensitivity measured by the intraperitoneal glucose tolerance test in fasted animals. Ectopic expression of the Acrp30 transgene resulted in modulation of hepatic gluconeogenesis and lipogenesis as demonstrated by the reduction in the hepatic expression of 2 key genes: PEPCK (614168) and SREBP1C (184756). Shklyaev et al. (2003) concluded that these data showed successful peripheral therapy in a clinically relevant model of human obesity and insulin resistance.
In ischemia-reperfusion studies in adiponectin-null mice, Shibata et al. (2005) observed increased myocardial infarct size, myocardial apoptosis, and TNF expression compared to wildtype mice. Administration of adiponectin diminished infarct size, apoptosis, and TNF production in both adiponectin-null and wildtype mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF production. Dominant-negative AMPK reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF production. Adiponectin induced COX2-dependent synthesis of prostaglandin E2 in cardiac cells, and COX2 inhibition reversed the inhibitory effects of adiponectin on TNF production and infarct size. Shibata et al. (2005) suggested that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX2-dependent mechanisms.
Using TUNEL analysis, Takemura et al. (2007) showed that Adipoq -/- mice were impaired in their ability to clear apoptotic thymocytes in response to dexamethasone treatment. Adipoq -/- mice also showed a reduced ability to clear injected apoptotic cells. Administration of adiponectin promoted macrophage-mediated clearance of apoptotic cells by both Adipoq -/- and wildtype mice. Overexpression of adiponectin facilitated apoptotic cell clearance and reduced expression of autoimmunity in lpr mice, which have a mutation in the Tnfrsf6 gene (134637) that leads to impaired clearance of dying cells. Adiponectin deficiency in lpr mice caused a further reduction in apoptotic cell clearance and exacerbated systemic inflammation. Flow cytometric, immunoprecipitation, and fluorescence microscopy analyses demonstrated that adiponectin opsonized apoptotic cells through interactions with Cd91 (LRP1; 107770) and phagocyte calreticulin (CALR; 109091). Takemura et al. (2007) concluded that there is a mechanistic link between insufficient adiponectin, obesity, and systemic inflammation, and that adiponectin functions to promote clearance of early apoptotic debris.
Noting that increased albuminuria is associated with obesity and diabetes, Sharma et al. (2008) studied 20 obese African American patients and found a statistically significant negative correlation between plasma adiponectin concentration and urinary albumin excretion (p less than 0.01). The authors then examined Adipoq-null mice and observed increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK (see 602739), and both adiponectin and AMPK activation reduced podocyte dysfunction and permeability to albumin, possibly due to the concomitant decrease in oxidative stress, as evidenced by reduction of Nox4 (605261) in podocytes. Adipoq-null mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of stress. Sharma et al. (2008) concluded that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.
Kasahara et al. (2012) observed increased bronchoalveolar lavage (BAL) levels of adiponectin in wildtype mice exposed to low-dose ozone. Following ozone exposure, Adipo -/- mice showed increased pulmonary inflammation, including augmented BAL neutrophils, BAL protein, Il6, Kc (CXCL1; 155730), Lix (CXCL5; 600324), and Gcsf (CSF3; 138970), compared with wildtype mice. Ozone also increased Il17a (603149) mRNA expression to a greater extent in Adipo -/- mice compared with wildtype mice. Administration of anti-Il17a attenuated increases in BAL neutrophils and Gcsf in Adipo -/- mice, but not in wildtype mice. Flow cytometric analysis demonstrated a greater increase in numbers of Cd11c (ITGAX; 151510)-negative macrophages and gamma-delta T cells expressing Il17a after ozone exposure in Adipo -/- mice compared with wildtype mice. Kasahara et al. (2012) proposed that adiponectin protects against neutrophil recruitment induced by extended low-dose ozone exposure by inhibiting induction and/or recruitment of IL17A in interstitial macrophages and gamma-delta T cells.
In a nonobese Japanese man with coronary artery disease, lung thrombosis, autoimmune disease, and a markedly low concentration (1.16 microg/ml) of plasma adiponectin (ADPOD; 612556), Takahashi et al. (2000) identified a 383C-T transition in exon 3 of the APM1 gene, resulting in an arg112-to-cys (R112C) substitution. One of his 4 children had the mutation and a low concentration of plasma adiponectin. No functional studies were reported.
In studies in NIH3T3 fibroblasts expressing the R112C mutation, Waki et al. (2003) demonstrated that the mutant adiponectin did not assemble into LMW trimers, resulting in impaired secretion from the cell.
In a family with low plasma adiponectin, type 2 diabetes, and end-stage renal disease (ADPOD; 612556), Simeone et al. (2022) detected a heterozygous 10-nucleotide deletion (CCCGAGGCTTT-C) in exon 3 of the ADIPOQ gene, resulting in a frameshift and premature termination of the adiponectin protein. This generates a novel peptide that terminates 73 amino acids after the deletion. Carriers of the mutation had significantly reduced circulating adiponectin, less than 20% of the levels found in noncarriers (p less than 0.05). Fast protein liquid chromatography (FPLC) and Western blot analysis of mutant and wildtype adiponectin revealed lack of high molecular weight (HMW) adiponectin complexes in carriers of the mutation, whereas HMW adiponectin was the most abundant isoform in the noncarriers. Additionally, carriers of the mutation had on average a 35% increase in C16.0 ceramide levels compared to noncarriers (p less than 0.037). Functional studies demonstrated that wildtype adiponectin and the mutant variant interacted, leading to decreased stability of the wildtype adiponectin. Simeone et al. (2022) suggested that the mutated adiponectin protein acts as a dominant negative through its interaction with nonmutated adiponectin, decreasing circulating adiponectin, and correlating with metabolic disease.
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