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Molecular basis of brain-mediated regulation of hepatic glucose metabolism

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Abstract

Various humoral factors are involved in the regulation of energy and glucose metabolism mediated by the interaction between the central nervous system and peripheral tissues. Insulin, which strictly regulates glucose metabolism in the liver, skeletal muscles, and adipose tissue, also plays a role in brain-mediated regulation of energy and glucose metabolism. Through the hypothalamus, insulin regulates not only diet intake and postprandial thermogenesis, but also glucose metabolism in the liver and skeletal muscles. Insulin exerts its action on the liver via the vagus nerve by activating phosphoinositide-3-kinase and KATP channels in the hypothalamic neurons. Central insulin action enhances the secretion of interleukin-6 from hepatic Kupffer cells and activates the transcription factor signal transducer and activator of transcription 3 (STAT3), which suppresses the expression of gluconeogenic enzyme genes in hepatocytes and thereby reducies hepatic glucose production. Brain-mediated suppression of hepatic glucose production also arises from an increase in the plasma histidine level. Histidine is converted to histamine in the hypothalamus, which activates hepatic STAT3 and thereby suppresses the expression of gluconeogenic enzyme genes via hypothalamic histamine H1 receptors. In obesity and type 2 diabetes, suppression of hepatic glucose production by central insulin action is impaired, potentially increasing hepatic glucose production. However, further studies are needed to elucidate the molecular mechanisms underlying the interaction between the central nervous system and peripheral tissues.

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Acknowledgments

This review was presented as a part of the Lilly Award Lecture at the Japan Diabetes Society 2014, Osaka, Japan. I would like to sincerely acknowledge the inspiring guidance and continued support of my mentor, Masato Kasuga. I also thank my colleagues and collaborators who have contributed to the work performed over the past 15 years. Finally, I would like to acknowledge the commitment and generosity of the Frontier Science Organization and the College of Medical, Pharmaceutical and Health Sciences of Kanazawa University. I thank ThinkSCIENCE, Inc. (Tokyo, Japan) for help preparing the manuscript. This work was supported by the Japan Society for the Promotion of Science KAKENHI Grant Numbers 25126709, 26282022, and 26670599, and by the Daininaika-Doumonkai grant to H.I.

Conflict of interest

I declare that I have no conflict of interest.

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  1. Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan

    Hiroshi Inoue

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Correspondence to Hiroshi Inoue.

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Inoue, H. Molecular basis of brain-mediated regulation of hepatic glucose metabolism. Diabetol Int 5, 158–164 (2014). https://doi.org/10.1007/s13340-014-0185-8

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