According to our adiponectin hypothesis (21
), a therapeutic strategy for the treatment of insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease may include the upregulation of plasma adiponectin levels, the upregulation of adiponectin receptors, or the development of adiponectin receptor agonists.
TZD-mediated upregulation of plasma adiponectin level
.TZDs are known to improve systemic insulin sensitivity in animal models of obesity-linked insulin resistance and diabetes, by enhancing glucose disposal in skeletal muscle and suppressing gluconeogenesis in the liver. TZDs have been widely used as therapeutic agents for the treatment of type 2 diabetes (94
). TZDs have been proposed to ameliorate insulin resistance by binding to and activating PPARγ in adipose tissue, thereby promoting adipocyte differentiation and increasing the number of small adipocytes that are more sensitive to insulin (100
).Plasma adiponectin levels have been shown to be upregulated by TZDs (58
) (Table ), and HMW adiponectin is a predominant form of adiponectin upregulated by TZDs (89
). TZDs may upregulate adiponectin by generating small adipocytes that abundantly express and secrete adiponectin (100
) and/or directly activating Adiponectin
gene transcription (106
). TZDs may also directly facilitate the generation of HMW adiponectin. Since adiponectin is an insulin-sensitizing adipokine, it is reasonable to speculate that the action whereby TZDs increase insulin sensitivity is mediated, at least in part, by increased plasma adiponectin levels. However, whether the TZD-induced increase in plasma adiponectin level is causally involved in TZD-mediated insulin-sensitizing effects has not been addressed experimentally. Adiponectin-deficient (Adipo–/–
mice with a C57BL/6 background were used to investigate whether the PPARγ agonist pioglitazone is capable of ameliorating insulin resistance in the absence of adiponectin (63
). The absence of adiponectin had no effect on either the obesity or the diabetic phenotype of these mice. The severity of insulin resistance and diabetes observed in ob/ob
mice was significantly reducedin association with significant upregulation of serum adiponectin levels by low-dose (10 mg/kg) pioglitazone treatment. Amelioration of insulin resistance in ob/ob
mice was attributed to decreased glucose production and increased AMPK levels in the liver, but not to increased glucose uptake in skeletal muscle. In contrast, the severity of insulin resistance and diabetes was not reducedin Adipo–/–ob/ob
). With high-dose pioglitazone treatment, the insulin resistance and diabetes of ob/ob
mice were again significantly ameliorated; this was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, Adipo–/–ob/ob
mice also displayed significant amelioration of insulin resistance and diabetes. The serum FFA and triglyceride levels as well as adipocyte sizes in ob/ob
mice were unchanged after low-dose pioglitazone treatment but were significantly reduced to a similar degree after high-dose pioglitazone treatment. Moreover, the expression of TNF-α and resistin in adipose tissues of ob/ob
mice were unchanged after low-dose pioglitazone but were decreased after high-dose pioglitazone. Although both high and low doses of pioglitazone ameliorated insulin resistance and diabetes, the underlying mechanisms may be different (87
). We propose that there are 2 different pathways in the amelioration of insulin resistance induced by TZDs such as pioglitazone, and probably rosiglitazone. One involves an adiponectin-dependent pathway and the other an adiponectin-independent pathway (Figure ). TZDs increase adiponectin levels via activation of Adiponectin
gene transcription without stimulating adipocyte differentiation (58
), thereby increasing AMPK activation, decreasing gluconeogenesis in the liver, and ameliorating insulin resistance and type 2 diabetes. On the other hand, independently of adiponectin, TZDs induce adipocyte differentiation, leading to an increase in the number of small adipocytes, which is associated with decreased serum FFA levels and decreased TNF-α and resistin expression, together contributing to amelioration of insulin resistance in skeletal muscle (87
TZDs ameliorate insulin resistance and diabetes by both adiponectin-dependent and -independent pathways.
Scherer’s group demonstrated that ob/ob
mice showed significantly improved glucose tolerance after rosiglitazone treatment, whereas Adipo–/–ob/ob
mice responded only partially to this treatment and remained severely glucose intolerant (66
), suggesting that rosiglitazone ameliorated glucose intolerance via both adiponectin-dependent and -independent pathways. Moreover, rosiglitazone significantly increased AMPK activity in the livers of wild-type mice, whereas it had no effect on Adipo–/–
mice. In skeletal muscle, AMPK activity was also significantly increased in wild-type mice, while no increase was detectable in Adipo–/–
mice. These data are in complete agreement with our data. Other pharmacological agents as well as lifestyle changes have also been reported to be associated with upregulation of plasma adiponectin levels (53
) (Table ).
Upregulation of adiponectin receptors and development of adiponectin receptor agonists
. Since AdipoR1 and AdipoR2 are downregulated in obesity-linked insulin resistance and diabetes, both upregulation of AdipoR1 and AdipoR2 expression and agonism of AdipoR1 and AdipoR2 may be a logical approach to providing a novel treatment modality for insulin resistance and type 2 diabetes (84
). Previously, Staels’s group reported that adiponectin receptors are expressed in human macrophages and that adiponectin receptor
expression levels may be regulated by agonists of the nuclear receptors PPARα, PPARγ, and liver X receptor (116
). We have recently shown that, in KKAy
mice, a PPARα agonist reversed decreases in AdipoR1 and AdipoR2 expression, which waslower in white and brown adipose tissue of KKAy
mice than in that of wild-type control KK mice (117
). These data suggested that dual activation of PPARγ and PPARα enhanced the action of adiponectin by increasing both total and HMW adiponectin level and adiponectin receptor number, which can ameliorate obesity-linked insulin resistance.
Osmotin is a member of the pathogenesis related-5 (PR-5) family of plant defense proteins (24 members in Arabidopsis thaliana
) that induce apoptosis in yeast. It is ubiquitous in fruits and vegetables, etc., and the genes encoding the PR-5 protein sequenced from many different species are about 50–95% identical. PR-5 family proteins are also extremely stable and may remain active even when in contact with the human digestive or respiratory system. Bressan’s group isolated a yeast clone that exhibited hypersensitivity to osmotin, sequenced the cDNA inserts, and found that PHO36/YOL002c, the yeast homologue of AdipoR1, is a receptor for osmotin (118
). X-ray crystallographic studies revealed that both globular adiponectin and osmotin consist of antiparallel β-strands arranged in the shape of a β-barrel. Domain I (lectinlike domain) of osmotin showed similarity to globular adiponectin in 3D structure, suggesting that these 2 proteins share the lectinlike domain (118
). Interestingly, osmotin activates AMPK via adiponectin receptors in mammalian C2C12 myocytes (118
). These data raise the possibility that further research examining similarities in adiponectin and osmotin may facilitate the development of potential adiponectin receptor agonists (118
). Although further studies will be needed to determine the physiological and pathophysiological roles of AdipoR1 and AdipoR2, the enhancement or mimicking of adiponectin action through modulation of expression and/or function of AdipoR1 and AdipoR2 can be a novel therapeutic strategy for the treatment of insulin resistance, the metabolic syndrome, and type 2 diabetes.
In summary, adiponectin is an adipokine that exerts a potent insulin-sensitizing effect by binding to its receptors such as AdipoR1 and AdipoR2, leading to activation of AMPK, PPARα, and presumably some other unknown signaling pathways. Indeed, circulating levels of adiponectin, especially HMW adiponectin, are positively correlated with insulin sensitivity and altered by various genetic and environmental factors, pathological conditions, and medications. Thus, monitoring the levels of HMW adiponectin is a good predictable marker for type 2 diabetes and the metabolic syndrome. Moreover, methods to increase adiponectin levels, such as TZD administration, are expected to be effective for the treatment of these diseases. In the future, enhancing or mimicking adiponectin action through modulation of expression and/or function of the adiponectin receptors may be a novel and promising therapeutic strategy for insulin resistance, type 2 diabetes, and the metabolic syndrome.