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 language | English |
|---|---|
| Pages (from-to) | 2372-2386 |
| Number of pages | 15 |
| Journal | Diabetes |
| Volume | 66 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 1 2017 |
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All Science Journal Classification (ASJC) codes
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
Activation of SF1 neurons in the ventromedial hypothalamus by DREADD technology increases insulin sensitivity in peripheral tissues. / Coutinho, Eulalia A.; Okamoto, Shiki; Ishikawa, Ayako Wendy; Yokota, Shigefumi; Wada, Nobuhiro; Hirabayashi, Takahiro; Saito, Kumiko; Sato, Tatsuya; Takagi, Kazuyo; Wang, Chen Chi; Kobayashi, Kenta; Ogawa, Yoshihiro; Shioda, Seiji; Yoshimura, Yumiko; Minokoshi, Yasuhiko.
In: Diabetes, Vol. 66, No. 9, 01.09.2017, p. 2372-2386.Research output: Contribution to journal › Article
}
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
PY - 2017/9/1
Y1 - 2017/9/1
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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UR - http://www.scopus.com/inward/citedby.url?scp=85028026576&partnerID=8YFLogxK
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 -