Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia.
The importance of neuropeptides in the hypothalamus has been experimentally established. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia.
Tong
Qingchun
Q
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA.
Ye
ChianPing
C
McCrimmon
Rory J
RJ
Dhillon
Harveen
H
Choi
Brian
B
Kramer
Melissa D
MD
Yu
Jia
J
Yang
Zongfang
Z
Christiansen
Lauryn M
LM
Lee
Charlotte E
CE
Choi
Cheol Soo
CS
Zigman
Jeffrey M
JM
Shulman
Gerald I
GI
Sherwin
Robert S
RS
Elmquist
Joel K
JK
Lowell
Bradford B
BB
D000818:Animals; D004594:Electrophysiology; D005934:Glucagon / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism*; D007031:Hypothalamus / Q000166:cytology*; D017403:In Situ Hybridization; D007328:Insulin; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013569:Synapses / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics
D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C493477:Slc17a6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D005934:Glucagon; D005952:Glucose-6-Phosphatase