TY - JOUR
T1 - Activation of SF1 neurons in the ventromedial hypothalamus by DREADD technology increases insulin sensitivity in peripheral tissues
AU - Coutinho, Eulalia A.
AU - Okamoto, Shiki
AU - Ishikawa, Ayako Wendy
AU - Yokota, Shigefumi
AU - Wada, Nobuhiro
AU - Hirabayashi, Takahiro
AU - Saito, Kumiko
AU - Sato, Tatsuya
AU - Takagi, Kazuyo
AU - Wang, Chen Chi
AU - Kobayashi, Kenta
AU - Ogawa, Yoshihiro
AU - Shioda, Seiji
AU - Yoshimura, Yumiko
AU - Minokoshi, Yasuhiko
N1 - Funding Information:
1Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Science, National Institutes of Natural Sciences, Okazaki, Aichi, Japan 2Department of Physiological Science, School of Life Sciences, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa, Japan 3Division of Visual Information Processing, Department of Fundamental Neuroscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, Japan 4Global Research Center for Innovative Life Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan 5Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 6Department of Human Life Science, Nagoya University of Economics, Inuyama, Aichi, Japan 7Center for Experimental Animals, National Institutes of Natural Sciences, Okazaki, Aichi, Japan 8Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, Japan 9Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan 10Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 11Japan Agency for Medical Research and Development, CREST (AMED-CREST), Tokyo, Japan Corresponding author: Yasuhiko Minokoshi, minokosh@nips.ac.jp. Received 2 November 2016 and accepted 8 June 2017. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1344/-/DC1. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.
Funding Information:
Acknowledgments. The authors thank Pavel Osten (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY) and Bryan L. Roth (Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina School of Medicine, Chapel Hill, NC) for viral vectors, Megumi Hayashi (Division of Endocrinology and Metabolism, National Institute for Physiological Sciences) for help with manuscript preparation, Rie Kageyama (Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences) for virus preparation, the Functional Genomics Facility at the National Institute for Basic Biology for DNA sequencing, and the Center for Radioisotope Facilities at the National Institute for Basic Biology for assistance with radioisotope experiments. Funding. This study was supported by the following grants from the Japan Society for the Promotion of Science: Grant-in-Aid for Scientific Research (C) (15K09405) to S.O., Grant-in-Aid for Scientific Research (B) (24390058) to Y.M., and Grant-in-Aid for Exploratory Research (15K15352) to Y.M. The study was supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan through a Grant-in-Aid for Scientific Research on Innovative Areas (22126005) to Y.M. and by the Core Research for Evolutional Science and Technology Program AMED-CREST of the Japan Science and Technology Agency and the Japan Agency for Medical Research and Development to Y.M. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. E.A.C. performed GTT and hyperinsulinemic-euglycemic clamp analyses. E.A.C. and S.O. performed the ITT and histological experiments. E.A.C., S.O., T.S., and K.K. prepared and evaluated viral vectors. E.A.C., S.Y., K.S., and C.-C.W. performed biochemical experiments. E.A.C. and K.T. performed energy expenditure experiments. E.A.C. and Y.M. designed the experiments, analyzed the data, and wrote the manuscript. A.W.I. and Y.Y. performed electrophysiological experiments. N.W., T.H., and S.S. supervised the histological experiments. Y.O. supervised the project. Y.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2017 by the American Diabetes Association.
PY - 2017/9
Y1 - 2017/9
N2 - The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine-N-oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulinemic-euglycemic clamp, such activation of SF1 neurons increased insulin-induced glucose uptake in the same peripheral tissues and tended to enhance insulin-induced suppression of glucose production by suppressing gluconeogenic gene expression and glycogen phosphorylase a activity in the liver. DREADD technology is thus an important tool for studies of the role of the brain in the regulation of insulin sensitivity in peripheral tissues.
AB - The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine-N-oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulinemic-euglycemic clamp, such activation of SF1 neurons increased insulin-induced glucose uptake in the same peripheral tissues and tended to enhance insulin-induced suppression of glucose production by suppressing gluconeogenic gene expression and glycogen phosphorylase a activity in the liver. DREADD technology is thus an important tool for studies of the role of the brain in the regulation of insulin sensitivity in peripheral tissues.
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U2 - 10.2337/db16-1344
DO - 10.2337/db16-1344
M3 - Article
C2 - 28673934
AN - SCOPUS:85028026576
VL - 66
SP - 2372
EP - 2386
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 9
ER -
