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Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases

International Journal of Obesity volume 32, pages S13–S18 (2008)Cite this article

Abstract

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.

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Acknowledgements

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).

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  1. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    T Yamauchi & T Kadowaki

  2. Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, University of Tokyo Hospital, University of Tokyo, Tokyo, Japan

    T Yamauchi

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Correspondence to T Kadowaki.

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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 (Suppl 7), S13–S18 (2008). https://doi.org/10.1038/ijo.2008.233

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