Adiponectin and adiponectin receptors (AdipoRs) have been found to play significant roles in the etiology of obesity-related chronic disease. Their discovery has been a long and complicated path, with many challenges. Developing methods to unravel the molecular secrets has been an informative process in itself. However, with both functional and genetic studies confirming adiponectin as a therapeutic target adipokine, many roles and interactions with certain other biomolecules have been clearly defined. We have found that decreased high molecular weight (HMW) adiponectin plays a crucial and causal role in obesity-linked insulin resistance and metabolic syndrome; that AdipoR1 and AdipoR2 serve as the major AdipoRs in vivo; and that AdipoR1 activates the AMP kinase (AMPK) pathway and AdipoR2, the peroxisome proliferator-activated receptor alpha (PPARα) pathway in the liver, to increase insulin sensitivity and decrease inflammation. Further conclusions are that decreased adiponectin action and increased monocyte chemoattractant protein-1 (MCP-1) form a vicious adipokine network causing obesity-linked insulin resistance and metabolic syndrome; PPARγ upregulates HMW adiponectin and PPARα upregulates AdipoRs; that dietary osmotin can serve as a naturally occurring adiponectin receptor agonist; and finally, that under starvation conditions, MMW adiponectin activates AMPK in hypothalamus, and promotes food intake, and at the same time HMW adiponectin activates AMPK in peripheral tissues, such as skeletal muscle, and stimulates fatty-acids combustion. Importantly, under pathophysiological conditions, such as obesity and diabetes, only HMW adiponectin was decreased; therefore, strategies to increase only HMW adiponectin may be a logical approach to provide a novel treatment modality for obesity-linked diseases, such as insulin resistance and type 2 diabetes. It is hoped that these data will be helpful in developing treatments to counteract the destructive, expensive and painful effects of obesity.
Lodish et al.1 reported a novel 30-kDa secretory protein, Acrp30 (adipocyte complement-related protein of 30 kDa), that is made exclusively in adipocytes and whose mRNA level is induced over 100-fold during adipocyte differentiation. Matsuzawa and colleagues2 reported cDNA cloning and expression of a novel adipose-specific collagen-like factor, apM1 (AdiPose most abundant gene transcript 1). Using an mRNA differential display technique, Spiegelman and colleagues.3 described an adipose cDNA, adipoQ, whose expression was highly specific to adipose tissue, and was reduced significantly in obesity. Tomita and colleagues4 reported a novel gelatin-binding protein, GBP28, purified from human plasma.
Adiponectin as a key mediator of obesity-linked insulin resistance and metabolic syndrome: adiponectin hypothesis
On the basis of the data that we and others have reported earlier, we are proposing an adiponectin hypothesis for insulin resistance, metabolic syndrome and atherosclerosis. According to this hypothesis, reduced adiponectin levels can be caused by genetic factors, such as the single nucleotide polymorphism 276 in the adiponectin gene itself. Reduced adiponectin levels can also be caused by lifestyle changes causing obesity, such as a high-fat diet. Both functional5, 6, 7 and genetic studies on adiponectin strongly suggest that reduced adiponectin levels play a causal role in the development of insulin resistance, metabolic syndrome, type 2 diabetes and atherosclerosis8, 9, 10, 11 (Figure 1).
We have earlier reported that AdipoR1 and R2 serve as receptors for adiponectin, and mediate increased AMP kinase (AMPK) activities,12, 13 peroxisome proliferator-activated receptor alpha (PPARα) activities,14 fatty-acid oxidation and glucose uptake by adiponectin in cultured cells, such as myocytes and hepatocytes15 (Figure 2).
To determine the physiological role of AdipoRs, we generated AdipoRs knockout mice.16 We confirmed that AdipoR1 or R2 knockout mice showed abrogation of AdipoR1 or R2 protein, respectively. In wild-type mice, adiponectin binds specifically to hepatocytes, whereas targeted disruption of both AdipoR1 and R2 completely abrogated adiponectin-specific binding to hepatocytes. Adiponectin was able to significantly lower plasma glucose levels in wild-type mice as we have reported earlier,12 whereas the glucose-lowering effect of adiponectin was completely abrogated in AdipoR1 and R2 double knockout mice. These data indicated that AdipoR1 and R2 serve as the major AdipoRs in vivo.16
AdipoR1 knockout mice and double knockout mice exhibited insulin resistance and impaired glucose tolerance, whereas AdipoR2 knockout mice exhibited insulin resistance without glucose intolerance. These data indicated that AdipoR1 and R2 play physiologically important roles in the regulation of insulin sensitivity and glucose metabolism in vivo.16
Adiponectin/MCP-1 network in obesity-linked insulin resistance and metabolic syndrome
A hypothesis entitled ‘Inflammation and insulin resistance in adipose tissue’ has been proposed by Wellen and Hotamisligil.17 According to their hypothesis, hypertrophic adipocytes, preadipocytes and endothelial cells may secrete monocyte chemoattractant protein-1 (MCP-1), which recruits macrophages, thereby inducing inflammation and insulin resistance.
We18 and Kasuga and colleagues of Kobe University19 generated transgenic mice overexpressing MCP-1 in adipocytes and reported that overexpression of MCP-1 in adipocytes induced macrophage infiltration and at the same time increased insulin resistance causing adipokines, such as tumor necrosis factor-α, interleukin-6 and free-fatty acids, which resulted in systemic insulin resistance (Figure 3).
We next examined the relationship between the insulin-sensitizing-adipokine adiponectin and the insulin resistance causing chemokine MCP-1. Simultaneous disruption of AdipoR1 and R2 resulted in increased MCP-1 expression levels and macrophage marker Mac-1 in white adipose tissue (WAT). These data suggested that decreased adiponectin signaling may serve as an upstream pathway of increased MCP-1 expression and inflammation in WAT.16
Disruption of AdipoR1 and R2 resulted in decreased levels of oxidative stress-scavenging enzymes, such as catalase and superoxide dismutase, which resulted in increased oxidative stress in WAT. These data suggested that decreased adiponectin signaling may serve as an upstream pathway of increased oxidative stress in WAT.16
In hypertrophic adipocytes observed in obesity, decreased adiponectin action and increased MCP-1 form a vicious adipokine network to cause obesity-linked insulin resistance and metabolic syndrome. Strategies to activate the adiponectin/AdipoRs pathway may provide a novel treatment modality for insulin resistance, metabolic syndrome and atherosclerosis16 (Figure 1).
High molecular weight (HMW) adiponectin as a novel biomarker for insulin resistance and metabolic syndrome
We have reported that SDS-polyacrylamide gel electrophoresis under nonreducing and nonheat-denaturing conditions is a very useful method, with which multimer formation of adiponectin is evaluated.20 Adiponectin migrates as a 28 kDa monomer under standard Laemmli conditions, that is, reducing heat-denaturing conditions. In contrast, when we did not include reducing reagent and did not boil the sample, adiponectin ran roughly as three MW groups, designated as HMW, middle MW and low MW multimers, respectively. The size of the HMW multimers exceeds 250 kDa. Further analysis showed that these bands represented various adiponectin homomultimers in the native state and the low MW species was a trimer.20
Patients with a mutation in the adiponectin gene (G90S) that decreases HMW adiponectin exhibit diabetes,20 raising the possibility that HMW adiponectin may serve as the most active multimeric form of adiponectin.
Obese KKAy mice show decreased HMW adiponectin compared with lean KK mice.22 We then developed an enzyme-linked immunosorbent assay for specific measurement of human HMW adiponectin.23 The HMW adiponectin/total adiponectin ratio is more tightly correlated with insulin resistance than total adiponectin. The HMW adiponectin/total adiponectin ratio is more useful than total adiponectin in the diagnosis of metabolic syndrome24 (Figure 4).
Development of novel therapeutic strategy targeting adiponectin
PPARγ upregulates HMW adiponectin
High molecular weight was downregulated in KKAy mice compared with KK mice.22 We next searched for strategies that could increase HMW adiponectin and found that a PPARγ agonist and energy restriction upregulated the reduced HMW adiponectin.22
Next, we attempted to clarify the relative contribution of adiponectin in the actions, such as antidiabetic effects, of a PPARγ agonist.25 In all, 10 mg kg−1 pioglitazone significantly ameliorated diabetes in ob/ob mice, but not in adiponectin deficient ob/ob mice. These data suggested that the PPARγ agonist ameliorated diabetes, at least in part, through an adiponectin-dependent pathway. In all, 30 mg kg−1pioglitazone significantly ameliorated diabetes to an apparently similar degree in ob/ob and adiponectin deficient ob/ob mice. These data suggested that PPARγ agonists could also ameliorate diabetes through an adiponectin-independent pathway. We next attempted to clarify the mechanisms, by which thiazolidinediones ameliorated insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. A low dose of thiazolidinediones increased adiponectin by stimulating transcription, whereas a high dose induced adipocyte differentiation, thereby decreasing adipocyte size, and at the same time reducing insulin resistance causing adipokines, such as free fatty acids, tumor necrosis factor-α and MCP-1, both of which ameliorated insulin resistance and diabetes25 (Figure 1).
Development of novel therapeutic strategy that could increase AdipoRs
PPARα upregulates AdipoRs
We have shown that the expression levels of adiponectin and AdipoR1/R2 are decreased in obesity.26 Decreased AdipoRs in obesity reduce adiponectin sensitivity, which ultimately leads to insulin resistance. Our data raised the possibility that not only agonism of AdipoR1/R2 but also strategies to increase AdipoR1/R2 may be a logical approach to provide a novel treatment modality for insulin resistance and type 2 diabetes.26 Expression levels of AdipoR1 and R2 were decreased in the liver of db/db mice.16
To clarify the pathophysiological roles of AdipoRs in vivo, we next studied the effects of adenovirus-mediated upregulation of AdipoRs in db/db mice.16 Threefold overexpression of AdipoR1 or fivefold overexpression of AdipoR2 in the liver of db/db mice ameliorated diabetes significantly. Importantly, these beneficial effects of increased AdipoR1/R2 were not observed in adiponectin-deficient db/db mice, suggesting that the AdipoR1/R2 effects depend on adiponectin.16
We hypothesized that AdipoR1 may exert its biological effects through AMPK, whereas AdipoR2 may exert them through PPARα. Moreover, AdipoR2 also seems to be linked to reductions in inflammation and oxidative stress, thereby increasing insulin sensitivity16 (Figure 5).
Next, we attempted to identify strategies that could increase AdipoRs, and found that a PPARα agonist upregulated the expressions of AdipoR1 and R2 in WAT of KKAy mice,22 whose expressions were reduced in obesity.26 PPAR agonists have been shown to reduce the expression levels of MCP-1, Mac-1 and tumor necrosis-α in WAT of KKAy mice.22
Our data suggest that dual activation of PPARγ and PPARα enhances the action of adiponectin by increasing both total and HMW adiponectin, and AdipoRs, which can result in amelioration of obesity-induced inflammation and insulin resistance22 (Figure 6).
Development of novel therapeutic strategy targeting AdipoRs
Osmotin can serve as AdipoR agonist
Osmotin is ubiquitous in fruits and vegetables. A group at Purdue University found that the receptor for osmotin was the yeast homolog of AdipoR1 (PHO36).27 X-ray crystallographic studies revealed that domain I of osmotin can be overlapped with globular adiponectin. These data prompted us to examine whether osmotin could activate AdipoRs in mammalian cells. We found that osmotin could activate AMPK in C2C12 myocytes. More importantly, suppression of AdipoRs expression by siRNA markedly reduced phosphorylation of AMPK induced by osmotin. These data suggested that osmotin seemed to activate AMPK through AdipoRs in mammalian C2C12 myocytes27 (Figure 4).
Osmotin is a member of the large pathogenesis-related protein family in plants, a family that is ubiquitous in fruits and vegetables. Other members may also activate mammalian AdipoRs. As pathogenesis-related proteins are extremely stable and may remain active when in contact with the human digestive system, they may be involved in the suppression of metabolic syndrome. These findings also raise the possibility that further research examining similarities in adiponectin and pathogenesis-related proteins, such as osmotin may facilitate the development of potential AdipoR agonists (Figure 4).
Adiponectin effects in the brain
Finally, we examined the effects of adiponectin in the brain.28 After feeding, serum leptin levels increase, which may lead to decreased hypothalamic AMPK activity and suppress food intake. In contrast, during fasting, serum adiponectin levels and AdipoR1 expressions in the arcuate hypothalamus increase, which may lead to increased hypothalamic AMPK activity and promote food intake. From these data, we hypothesized that adiponectin serves as a starvation gene. Under starvation conditions, adiponectin, especially middle MW adiponectin, inhibits energy expenditure and promotes food intake centrally, and at the same time HMW adiponectin in particular stimulates free-fatty acid utilization in peripheral tissues28 (Figures 2 and 5).
We identified adiponectin as a therapeutic target adipokine for insulin resistance, metabolic syndrome, diabetes and atherosclerosis by using the combination of genome-wide scanning and DNA chips. Genetic studies on single nucleotide polymorphisms of the adiponectin gene, as well as functional analyses, including transgenic or knockout mice suggested that reduced adiponectin levels play a causal role in the development of insulin resistance, metabolic syndrome, diabetes and atherosclerosis.8, 9, 10, 11 Moreover, human adiponectin mutation analysis20 led to the identification of HMW adiponectin as the most active form.21 We then developed an enzyme-linked immunosorbent assay system and showed that measurement of HMW is useful for the prediction of insulin resistance and metabolic syndrome.24 Recently, we showed that adiponectin also centrally regulates energy expenditure and food intake.28
We also identified AdipoRs (AdipoR1 and R2) by expression cloning,15 and found that AdipoRs are also decreased in obesity.26 Overexpression by adenoviruses suggested that strategies to increase AdipoRs should serve as treatment strategies for insulin resistance, metabolic syndrome, diabetes and atherosclerosis. Moreover, network analyses revealed that AdipoR1 may be tightly linked to the activation of the AMPK pathway, whereas AdipoR2 may be tightly linked to the activation of the PPARα pathway in the liver. Simultaneous disruption of both AdipoR1 and R2 revealed that they serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism.16 In WAT, simultaneous disruption of both AdipoR1 and R2 resulted in decreased oxidative stress-detoxifying enzymes, such as catalase and superoxide dismutase, and at the same time increased oxidative stress. Moreover, AdipoR deficiency also resulted in increased MCP-1 expression and macrophage infiltration. These data suggested that AdipoR1 and R2 also play important roles in the regulation of oxidative stress and inflammation in vivo.16
Finally, we showed that a PPARγ agonist upregulated total and HMW adiponectin, whereas a PPARα agonist upregulated AdipoRs.22 Moreover, we showed that osmotin, which is present in fruits and vegetables, activated AMPK through AdipoRs in myocytes.27
We are now screening for low molecular compounds, and for confirming the clinical effectiveness and usefulness of HMW measurement (Figure 4).
Decreased HMW adiponectin plays a crucial and causal role in obesity-linked insulin resistance and metabolic syndrome.
AdipoR1 and R2 serve as the major AdipoRs in vivo.
AdipoR1 activates the AMPK pathway and AdipoR2 activates the PPARα pathway, thereby causing increased insulin sensitivity and decreased inflammation.
Decreased adiponectin action and increased MCP-1 form a vicious adipokine network to cause obesity-linked insulin resistance and metabolic syndrome.
PPARγ upregulates HMW adiponectin and PPARα upregulates AdipoRs.
Osmotin in fruits and vegetables can serve as a naturally occurring AdipoR agonist.
During fasting, serum adiponectin levels and AdipoR1 expressions in the arcuate hypothalamus increase, which may in turn lead to an increased hypothalamic AMPK activity and promote food intake.
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We thank K Ueki, K Hara, N Kubota, M Iwabu, M Iwabu-Okada, T Shimizu and R Nagai for their advice and helpful discussions. This study was supported by a grant from the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan (to TK), a grant-in-aid for the Development of Innovative Technology from the Japanese Ministry of Education, Culture, Sports, Science and Technology (to TK) and Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Japanese Ministry of Health, Labour and Welfare (to TK and TY).
Conflict of interest
The authors have declared no financial interests.
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Yamauchi, T., Kadowaki, T. Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes 32, S13–S18 (2008). https://doi.org/10.1038/ijo.2008.233
- type 2 diabetes
- insulin resistance
- HMW adiponectin
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