The brain requires glucose for its normal physiologic function. It has evolved glucosensing neurons which both sense and regulate peripheral glucose metabolism and energy homeostasis. Glucose responsive (GR) neurons increase their firing rate as ambient glucose levels rise whereas glucose sensitive (GS) neurons lower their firing rate as glucose levels rise. Our previous studies have identified some of the physiologic functions of these neurons and their responses to pathological states such as type 1 and 2 diabetes mellitus. This proposal will continue those studies to further delineate the function of these neurons in health and disease.
The specific aims follow 2 hypotheses. Hypothesis I: Glucosensing neurons represent a unique class of sensor-integrator-effector neurons involved in the regulation of energy homeostasis.
Specific Aim I : Use Ca+2 imaging combined with single cell polymerase chain reaction (SC-PCR), as well as in situ hybridization and immunocytochemistry with c-fos expression, to characterize arcuate (ARC), ventromedial nucleus (VMN) and substantial nigra (SN) GR and GS neurons by their response to and/or expression of components of the glucosensing mechanism, glucose, sulfonylureas, potassium channel openers, neuropeptides and neurotransmitters.
Specific Aim II : Characterize the response of SN DA neurons to systemic hyper- vs. hypoglycemia using microdialysis.
Specific Aim III : Use Ca2+ imaging with SC-PCR, in situ hybridization plus immunocytochemistry and microdialysis to characterize the effects of type I and type II diabetes on the molecular and functional properties of glucosensing neurons. Hypothesis II: Because ARC GR neurons use glucose as a signaling molecule acting at the KATP channel to sense glucose, they are selectively vulnerable to conditions which limit energy substrates as a source of intracellular ATP and to toxins that selectively target GR neurons.
Specific Aim I V: Verify that a single bout of hypoglycemia produces apoptosis in ARC neurons using other markers of apoptosis. Then demonstrate the phenotype of apoptotic cells and that functional markers of ARC glucosensing (c-fos expression to systemic hyper- or hypoglycemia) are attenuated in such animals. Finally, show that these changes cannot be prevented by lactate or pyruvate.
Specific Aim V : Demonstrate that brain glucosensing neurons are the target of toxins known to destroy pancreatic beta-cells (alloxan) and ARC neurons (gold thioglucose) using molecular and functional tests.
| Levin, Barry E (2017) 10 lessons learned by a misguided physician. Physiol Behav 176:217-222 |
| Otlivanchik, Oleg; Sanders, Nicole M; Dunn-Meynell, Ambrose et al. (2016) Orexin signaling is necessary for hypoglycemia-induced prevention of conditioned place preference. Am J Physiol Regul Integr Comp Physiol 310:R66-73 |
| Le Foll, Christelle; Dunn-Meynell, Ambrose A; Miziorko, Henry M et al. (2015) Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats. Am J Physiol Regul Integr Comp Physiol 308:R872-8 |
| Magnan, Christophe; Levin, Barry E; Luquet, Serge (2015) Brain lipid sensing and the neural control of energy balance. Mol Cell Endocrinol 418 Pt 1:3-8 |
| Le Foll, Christelle; Dunn-Meynell, Ambrose A; Levin, Barry E (2015) Role of FAT/CD36 in fatty acid sensing, energy, and glucose homeostasis regulation in DIO and DR rats. Am J Physiol Regul Integr Comp Physiol 308:R188-98 |
| Le Foll, Christelle; Dunn-Meynell, Ambrose A; Miziorko, Henri M et al. (2014) Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids. Diabetes 63:1259-69 |
| Song, Zhilin; Levin, Barry E; Stevens, Wanida et al. (2014) Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensors. Am J Physiol Regul Integr Comp Physiol 306:R447-56 |
| Le Foll, Christelle; Dunn-Meynell, Ambrose; Musatov, Serguei et al. (2013) FAT/CD36: a major regulator of neuronal fatty acid sensing and energy homeostasis in rats and mice. Diabetes 62:2709-16 |
| McNay, Ewan C; Teske, Jennifer A; Kotz, Catherine M et al. (2013) Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity without hyperphagia or insulin resistance: a model for weight gain with intensive insulin therapy. Am J Physiol Endocrinol Metab 304:E131-8 |
| Moullé, Valentine S; Le Foll, Christelle; Philippe, Erwann et al. (2013) Fatty acid transporter CD36 mediates hypothalamic effect of fatty acids on food intake in rats. PLoS One 8:e74021 |
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