Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues

Author:

Coutinho Eulalia A.12,Okamoto Shiki12,Ishikawa Ayako Wendy23,Yokota Shigefumi1,Wada Nobuhiro45,Hirabayashi Takahiro4,Saito Kumiko1,Sato Tatsuya1,Takagi Kazuyo16,Wang Chen-Chi27,Kobayashi Kenta28,Ogawa Yoshihiro91011,Shioda Seiji4,Yoshimura Yumiko23,Minokoshi Yasuhiko12ORCID

Affiliation:

1. Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Science, National Institutes of Natural Sciences, Okazaki, Aichi, Japan

2. Department of Physiological Science, School of Life Sciences, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa, Japan

3. Division of Visual Information Processing, Department of Fundamental Neuroscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, Japan

4. Global Research Center for Innovative Life Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan

5. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

6. Department of Human Life Science, Nagoya University of Economics, Inuyama, Aichi, Japan

7. Center for Experimental Animals, National Institutes of Natural Sciences, Okazaki, Aichi, Japan

8. Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi, Japan

9. Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

10. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

11. Japan Agency for Medical Research and Development, CREST (AMED-CREST), Tokyo, Japan

Abstract

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.

Funder

Japan Society for the Promotion of Science

Ministry of Education, Culture, Sports, Science, and Technology of Japan

Core Research for Evolutional Science and Technology Program (CREST) of the Japan Science and Technology Agency and the Japan Agency for Medical Research and Development

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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