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Publication : Altered Central Nutrient Sensing in Male Mice Lacking Insulin Receptors in Glut4-Expressing Neurons.

First Author  Ren H Year  2019
Journal  Endocrinology Volume  160
Issue  9 Pages  2038-2048
PubMed ID  31199472 Mgi Jnum  J:279774
Mgi Id  MGI:6343466 Doi  10.1210/en.2019-00341
Citation  Ren H, et al. (2019) Altered Central Nutrient Sensing in Male Mice Lacking Insulin Receptors in Glut4-Expressing Neurons. Endocrinology 160(9):2038-2048
abstractText  Insulin signaling in the central nervous system influences satiety, counterregulation, and peripheral insulin sensitivity. Neurons expressing the Glut4 glucose transporter influence peripheral insulin sensitivity. Here, we analyzed the effects of insulin receptor (IR) signaling in hypothalamic Glut4 neurons on glucose sensing as well as leptin and amino acid signaling. By measuring electrophysiological responses to low glucose conditions, we found that the majority of Glut4 neurons in the ventromedial hypothalamus (VMH) were glucose excitatory neurons. GLUT4-Cre-driven insulin receptor knockout mice with a combined ablation of IR in Glut4-expressing tissues showed increased counterregulatory response to either 2-deoxyglucose-induced neuroglycopenia or systemic insulin-induced hypoglycemia. The latter response was recapitulated in mice with decreased VMH IR expression, suggesting that the effects on the counterregulatory response are likely mediated through the deletion of IRs on Glut4 neurons in the VMH. Using immunohistochemistry in fluorescently labeled hypothalamic Glut4 neurons, we showed that IR signaling promoted hypothalamic cellular signaling responses to the rise of insulin, leptin, and amino acids associated with feeding. We concluded that hypothalamic Glut4 neurons modulated the glucagon counterregulatory response and that IR signaling in Glut4 neurons was required to integrate hormonal and nutritional cues for the regulation of glucose metabolism.
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