The brain senses and regulates glucose metabolism using unique glucosensing (GS) neurons which use glucose to regulate their firing rates. These neurons are critical components of the counterregulatory response (CRR) to hypoglycemia experienced by many insulin-requiring, Type 1 diabetics. However, it is still uncertain what role the interaction between GS neurons and changes in brain glucose levels within the physiologic range play in the regulation of food intake, sympathetic activation or thermogenesis. We postulate that glucokinase (GK) is a critical regulator of neuronal GS in the hypothalamic ventromedial (VMN) and arcuate (ARC) nuclei (together called the VMH) under both physiologic and pathologic conditions.
Specific Aim 1 will examine the effects of manipulating and measuring (by microdialysis) VMH glucose within the physiologic range in vivo both extrinsically (intracarotid glucose or stepped hypoglycemic hyperinsulinemic clamps) or intrinsically through reverse VMH microdialysis on feeding behavior, CRR (plasma catecholamines, glucagon, corticosterone) and brown adipose tissue temperature (via implanted telemetry probes) in vivo.
Specific Aim 2 will assess how in vitro pharmacologic and molecular (RNA interference [RNAi]) GK activation and inhibition of dissociated and cultured VMH GS neurons alters their sensitivity to glucose using calcium and membrane potential fluorescent imaging coupled with single cell, real-time (quantitative) rt-PCR (scQPCR). The effects of in vivo and in vitro hypoglycemia on GS neuron function and the expression of GK and other potential GS candidates will also be assessed. Other studies will manipulate VMH GK expression pharmacologically and with adenovirus expressing GK siRNA to evaluate the changes in CRR response to insulin-induced hypoglycemia and the development of hypoglycemia-associated autonomic failure.
Specific Aim 3 will explore alternate non-GK mechanisms of neuronal GS and Specific Aim 4 will pursue our finding that GS neurons can use fatty acids as signaling molecules. Both of these Specific Aims will be carried out in dissociated and cultured neurons using calcium imaging combined with scQPCR, drugs and RNAi. Finally, rats which develop diet-induced obesity (DIO) associated with insulin resistance when fed high energy (HE) 31% fat diets have abnormalities of neuronal GS. We will examine the physiologic and molecular characteristics of VMN and ARC neurons from DIO vs. diet-resistant rats fed low and HE diets to identify potential sites responsible for their abnormalities of GS and potential defects in fatty acid sensing to explain their propensity to become obese and insulin resistant on HE diet. ? ?
| 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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