Specialized metabolic sensing neurons in the arcuate (ARC) and ventromedial hypothalamic nucleus (VMN) utilize both glucose and long chain fatty acids (LCFA) as signaling molecules to alter their activity. These neurons are known to be involved in the regulation of the counterregulatory responses (CRR) to insulin- induced hypoglycemia (IIH), energy and glucose homeostasis in the body. We have identified glucokinase (GK) as a neuron-specific regulator of neuronal glucosensing and the FA receptor/transporter CD36 as a regulator of neuronal FA sensing. Manipulating GK activity in the ventromedial hypothalamus ((VMH: ARC + VMN) markedly alters the CRR to IIH and glucoprivic feeding but lowering it had no effect on energy homeostasis or glucose tolerance in rats fed low, low sucrose diets. However, rats selectively bred to develop diet-induced obesity (DIO) on a 31% fat, high sucrose, high energy (HE) diet have an inborn elevation of ARC GK in association with altered numbers of glucose and FA sensing VMN neurons, hyperphagia when exposed to HE diet and a blunted CRR to IIH as compared to selectively bred diet-resistant (DR) rats. Using DIO, DR and outbred rats and mice with fluorescently tagged neuropeptide Y (NPY) and proopiomelanocortin POMC) neurons or CD36 deletion, we will utilize calcium imaging, quantitative PCR, in vivo assessment of CRR, energy and glucose homeostasis to pursue the Overall Hypothesis that GK and CD36 are critical regulators of metabolic sensing in ARC and VMN neurons and that sensing of these substrates is critical for the modulation and blunting of the CRR to IIH, the development of hyperphagia and obesity on HE diet and glucose production and disposal.
Aim 1 will assess the role that GK plays in regulating glucosensing in identified ARC NPY and POMC neurons in mice and DIO and DR rats and assess the effect of lowering VMH GK activity to prevent the blunted CRR following repeated bouts of IIH. Also, since selective serotonin reuptake inhibitors increase the CRR and counteract its blunting, we will investigate the role of VMH serotonin in regulating the CRR and the expression of GK.
Aim 2 will assess the role of VMH GK in the regulation of sympathetic activity, hepatic glucose production, energy homeostasis and development of obesity in DIO vs. DR rats by altering its expression with adenoviral vectors.
Aim 3 will investigate the mechanisms by which ARC neurons sense various LCFA and use adeno-associated viral vectors to reduce the VMH expression of CD36, a LCFA receptor-transporter that we have shown regulates 50% of neuronal FA sensing, to assess the effects on both the CRR to IIH and the development of obesity in DIO vs. DR rats on high fat, high sucrose diets. The overall goal is to identify molecular targets involved in the regulation of glucose and FA sensing, that also affect energy and glucose homeostasis, as potential therapeutic targets to prevent blunting of the CRR in diabetics and the development of obesity and insulin resistance in humans on high fat, high sucrose diets.

Public Health Relevance

There is a world-wide epidemic of obesity and diabetes which causes significant morbidity and mortality. Neural circuits within the hypothalamus are critical regulators of energy and glucose balance and many are adversely affected by intake of a high fat, high sucrose diet. This project will identify the mechanisms by which the activity of hypothalamic neurons is regulated by glucose and fatty acids in vitro and during insulin-induced hypoglycemia and the development of obesity and insulin resistance in vivo. The ultimate goal is to identify potential therapeutic target molecules to prevent the adverse effects of recurrent hypoglycemia in diabetics and obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Teff, Karen L
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Veterans Biomedical Research Institute
East Orange
United States
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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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