Activation of SF1 neurons in the ventromedial hypothalamus by DREADD technology increases insulin sensitivity in peripheral tissues

Eulalia A. Coutinho, Shiki Okamoto, Ayako Wendy Ishikawa, Shigefumi Yokota, Nobuhiro Wada, Takahiro Hirabayashi, Kumiko Saito, Tatsuya Sato, Kazuyo Takagi, Chen Chi Wang, Kenta Kobayashi, Yoshihiro Ogawa, Seiji Shioda, Yumiko Yoshimura, Yasuhiko Minokoshi

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2372-2386
Number of pages15
JournalDiabetes
Volume66
Issue number9
DOIs
Publication statusPublished - Sep 2017

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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