Estradiol impairs hypothalamic molecular responses to hypoglycemia.
In rats and humans estradiol attenuates neuroendocrine responses to hypoglycemia. Since neuroendocrine responses to hypoglycemia are mediated by hypothalamic neurons, we assessed if estradiol attenuates hypoglycemia-induced gene expression in the hypothalamus in female ovariectomized mice. As expected, estradiol-implanted ovariectomized mice exhibited increased plasma estradiol, increased uterine weight, decreased body weight, decreased visceral adiposity, and enhanced glucose tolerance with decreased plasma insulin. Estradiol-implanted mice exhibited attenuated hypoglycemia-induced gene expression of both glucose transporter 1 (Glut1) and inhibitor of kappa beta signaling (IkappaB) in the hypothalamus but not in the liver. Estradiol also attenuated hypoglycemia-induced plasma glucagon, pituitary proopiomelanocortin (POMC), and adrenal c-fos, consistent with impaired counterregulatory responses to hypoglycemia. In addition, estradiol inhibited hypothalamic expression of carnitine palmitoyltransferase (CPT1a and CPT1c) and pyruvate dehydrogenase kinase 4 (PDK4), effects that would be expected to enhance the accumulation of long-chain fatty acids and glycolysis. Taken together, these findings suggest hypothalamic mechanisms mediating attenuation of hypoglycemia-induced neuroendocrine responses.
Cheng
Hui
H
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
Isoda
Fumiko
F
Mobbs
Charles V
CV
D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D004967:Estrogens / Q000097:blood / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D007003:Hypoglycemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010052:Ovariectomy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011897:Random Allocation; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D004967:Estrogens; D051272:Glucose Transporter Type 1; D020672:I-kappa B Proteins; D007328:Insulin; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C495678:Slc2a1 protein, mouse; D004958:Estradiol; D002334:Carnitine O-Palmitoyltransferase; D017346:Protein Serine-Threonine Kinases