Possible new therapeutic approach for obesity-related diseases: Role of adiponectin receptor agonists.

Adiponectin is a major adipokine that seems to have a crucial role in the protection from many metabolic abnormalities. There have been several reports that suggest a strong inverse relationship between plasma levels of adiponectin and the severity of obesity and its comorbidities, such as insulin resistance, type 2 diabetes and cardiovascular disease. Restoring adiponectin levels has salient benefits in many of the obesity-related diseases, which provides a strong rationale for adiponectin-based therapeutics for treating metabolic abnormalities. A Japanese team of researchers has screened and identified an orally active compound that binds to and activates the adiponectin receptor 1 (AdipoR1) and AdipoR2 receptors that are named AdipRon. This molecule ameliorates insulin resistance and glucose intolerance in obese animal models, and also extends the shortened lifespan of diabetic obese mice. If this work can be extended to humans, the improved safety and efficacy of these orally active adiponectin agonists could offer a promising new approach to treating obesity-related diseases.

Adiponectin, a fat-derived hormone, has been shown to play a critical role in the maintenance of metabolic homeostasis1. A decreased plasma adiponectin level has been linked to a wide variety of metabolic abnormalities, including obesity and associated disorders, such as insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular disease. Restoring the adiponectin level corrects these abnormalities, as shown by the striking metabolic benefits observed in genetic overexpression studies or by administration of recombinant adiponectin. This provides a strong rationale in its role as a therapeutic target for the treatment of a range of metabolic disorders, such as diabetes mellitus, obesity, inflammation and atherosclerosis2. Okada-Iwabu et al.3 identified an orally synthetic small-molecule adiponectin receptor agonist, named AdipRon, that binds to and activates the adiponectin receptor 1 (AdipoR1) and AdipoR2 receptors that mediate adiponectin's antidiabetic action.

Adiponectin is produced predominantly by adipocytes, and has emerged as a major adipokine with insulin sensitizing, anti-inflammatory, anti-atherogenic, tumor-suppressive and cardiovascular protective functions. Therefore, it appears to play a crucial role in metabolic and cardiovascular homeostasis, and is expected to be a therapeutic tool for diabetes, metabolic syndrome, cardiovascular diseases and cancers1. In the past 10 years, the receptors, AdipoR1 and AdipoR2, were identified by expression cloning. Disruption of AdipoR1 and AdipoR2 showed that AdipoR1 and AdipoR2 are required for specific binding of adiponectin, showing that AdipoR1 and AdipoR2 are major adiponectin receptors in vivo. Furthermore, postreceptor signaling mechanisms downstream of AdipoR1 and AdipoR2 through adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs) have also been progressively elucidated4. Plasma adiponectin levels have been reported to be reduced in obese humans, and hypoadiponectinemia has also been shown to have causal roles in the development of obesity-related diseases, such as diabetes and cardiovascular diseases. Recent prospective and longitudinal studies have shown that the reduction of plasma concentrations of adiponectin is not only closely related to disease states, such as type 2 diabetes and cardiovascular diseases, but is also implicated in cancer development in human obesity2. Consistent with the aforementioned clinical observations, numerous studies in different animal models, as well as in cell culture systems, have repeatedly reported the multiple protective effects of adiponectin against obesity-related medical complications and replenishment of recombinant adiponectin or transgenic expression of adiponectin can reverse these obesity-related pathological conditions. Combination of these expression profiles and epidemiological association studies between low adiponectin and clinical parameters, as well as functional analyses using transgenic or knockout mice, led to provide a strong rationale for adiponectin-based therapeutics for treating obesity-related diseases4.

From the recent reports, there are two strategies to reverse reduced adiponectin effects2. One is to increase circulating levels of adiponectin by induction of gene expression or protein mimetic approaches. Currently, intensive lifestyle modifications and several agents (e.g., PPAR-γ or PPAR-α agonists, some statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, some calcium channel blockers and several natural compounds) have been shown to be effective in increasing circulating adiponectin levels. However, most of them do so in a non-selective manner. Injection of recombinant adiponectin will be a challenging therapeutic strategy for these diseases in the future, despite some studies that have shown no effect of recombinant adiponectin in animals. An alternative strategy is to activate adiponectin receptors or modulate downstream effectors, such as AMPK. Both AdipoR1 and AdipoR2 have roles in the regulation of glucose, and lipid metabolism, inflammation and oxidative stress in vivo4. Therefore, the development of orally active small-molecule agonists for both AdipoR1 and AdipoR2 has long been sought. These findings led the Japanese investigators to try to identify compounds that could bind to and activate the adiponectin receptors.

Okada-Iwabu et al.3 screened a number of synthetic small molecules, and carried out functional assays to determine whether they could activate AMPK, calcium signaling and mitochondrial function. These experiments used Adipor1−/− Adipor2−/− double-knockout mice and Adipor1−/− or Adipor2−/− single-knockout mice, and identified an adiponectin receptor agonist – AdipoRon – that works through both AdipoR1 and AdipoR2 in vivo. In obese diabetic mice on a high-fat diet, AdipoRon exerted multiple effects very similar to those of adiponectin, including reduced tissue triglyceride content in the liver and muscle, and oxidative stress in the liver, muscle and white adipose tissues (WAT), and decreased inflammation in the liver and WAT that mediate through the AMPK and PPAR-α pathways. These alterations collectively result in increased insulin sensitivity and glucose tolerance, as well as suppression of cardiovascular diseases and cancer, as previously reported. AdipoRon also increased exercise endurance and prolonged the shortened lifespan of obese diabetic mice. Okada-Iwabu et al.3 provided evidence that an orally available synthetic small-molecule AdipoR agonist, such as AdipoRon, at doses achievable in vivo can reduce many of the unhealthy and undesirable consequences of excess calorie intake and sedentary lifestyle. Thus, AdipoRon is a promising therapeutic approach for obesity-related diseases, much like calorie restriction and exercise.

Taken together, Okada-Iwabu et al.3 showed that the orally active small-molecule AdipoR agonist, AdipoRon, shifts the physiology of mice fed excess calories towards that of mice fed a standard diet, modulates known longevity pathways, improves health and prolongs lifespan. These findings suggest that AdipoRon, besides adiponectin, can be a potential therapeutic agent for the treatment of insulin resistance and type 2 diabetes. Because all current therapeutic modalities of type 2 diabetes require intensive diet and exercise lifestyle modifications, AdipoRon provides a novel treatment modality5. However, the safety, toxicity and potential long-term side-effects of these initial compounds have not yet been determined in human studies. Some obvious physiological differences in the role of adiponectin between mice and humans have previously been reported. Furthermore, Okada-Iwabu et al.3 are now intending to optimize the adiponectin receptor agonists they have identified by studying the 3-D structure of the AdipoRon–adiponectin receptor complex, and are also planning to improve the safety and efficacy of these agonists5. Once the orally-active small molecule can be extended to humans, it could offer a promising new approach to treating obesity-related diseases, such as metabolic syndrome, type 2 diabetes, cardiovascular diseases, cancer and so on (Figure1).

Figure 1

Possible new therapeutic strategy to increase adiponectin effects. Obesity or obesity-related diseases may cause and associate with decreased adiponectin effects. There are several strategies to increase adiponectin effects. In clinics, exercise may have beneficial effects on healthy longevity and lifestyle related diseases through increased activation of adiponectin and adiponectin receptors pathways. Recently, Okada-Iwabu and colleagues3 developed oral active adiponectin agonists and this molecule ameliorates insulin resistance and glucose intolerance in obese animal models and also extends the shortened lifespan of diabetic obese mice. Once, the orally active small-molecule can be extended to humans that could offer a promising new approach to treat obesity-related diseases, such as metabolic syndrome, type 2 diabetes, cardiovascular diseases, cancer and so on.