Genomes and Genes
BRAIN GLUCOSENSING NEURONS IN HEALTH AND DIABETES
Principal Investigator: Barry Levin
Affiliation: New Jersey
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: ----------------1998 - ---------------2015-
more information: NIH RePORT
- Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensingLing Kang
Department of Neurology and Neuroscience, New Jersey Medical School, Newark, USA
Diabetes 55:412-20. 2006..98 mmol/l) and a decrease in glucose-inhibited neurons (IC(50) = 0.025 micromol/l) held at 0.5 mmol/l glucose. Together, these data support a critical role for glucokinase in neuronal glucosensing...
- Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acidsChristelle Le Foll
Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ
Diabetes 63:1259-69. 2014..These data suggest that a restricted HFD intake regimen inhibits caloric intake as a consequence of FA-induced VMH ketone body production by astrocytes. ..
- FAT/CD36: a major regulator of neuronal fatty acid sensing and energy homeostasis in rats and miceChristelle Le Foll
Department of Neurology and Neurosciences, New Jersey Medical School, Newark, New Jersey, USA
Diabetes 62:2709-16. 2013..These results demonstrate that CD36 is a critical factor in both VMH neuronal FA sensing and the regulation of energy and glucose homeostasis...
- Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensorsZhilin Song
Department of Physiology, University of Colorado School of Medicine, Aurora, Colorado
Am J Physiol Regul Integr Comp Physiol 306:R447-56. 2014..The findings are consistent with SON oxytocin and vasopressin neurons functioning as glucose and "metabolic" sensors to participate in appetite regulation...
- Epigenetic influences on food intake and physical activity level: review of animal studiesBarry E Levin
Neurology Service, VA Medical Center, East Orange, New Jersey, USA
Obesity (Silver Spring) 16:S51-4. 2008..Because perinatal manipulations can permanently alter the systems which regulate energy homeostasis, it behooves us to identify the responsible factors as a means of stemming the tide of the emerging worldwide obesity epidemic...
- Feeding and neuroendocrine responses after recurrent insulin-induced hypoglycemiaNicole M Sanders
Division of Endocrinology Metabolism, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
Physiol Behav 87:700-6. 2006..Thus, neuroendocrine and behavioral (stimulation of food intake) CRR are differentially regulated by recurrent hypoglycemia experience...
- Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemiaBarry E Levin
Neurology Service, Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018 1095, USA
Diabetes 57:1371-9. 2008....
- Effects of leptin on rat ventromedial hypothalamic neuronsBoman G Irani
Department of Neurology and Neurosciences, New Jersey Medical School, Newark, NJ 07103, USA
Endocrinology 149:5146-54. 2008..ARC neurons, and acts on both glucosensing and non-glucosensing VMN neurons in a glucose-independent fashion with inhibition primarily dependent upon activation of the ATP-sensitive K+ channel...
- Relationship among brain and blood glucose levels and spontaneous and glucoprivic feedingAmbrose A Dunn-Meynell
Neurology Service, Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USA
J Neurosci 29:7015-22. 2009....
- Peripheral glucose homeostasis: does brain insulin matter?Barry E Levin
Neurology Service 127C, VA Medical Center, East Orange, New Jersey 07018, USA
J Clin Invest 121:3392-5. 2011....
- Metabolic sensing and the brain: who, what, where, and how?Barry E Levin
Neurology Service 127C, Veterans Affairs Medical Center, 385 Tremont Avenue, East Orange, New Jersey 07018, USA
Endocrinology 152:2552-7. 2011..Thus, these specialized neurons are capable of monitoring and integrating multiple signals from the periphery as a means of regulating peripheral energy homeostasis...
- The medial amygdalar nucleus: a novel glucose-sensing region that modulates the counterregulatory response to hypoglycemiaLigang Zhou
Department of Internal Medicine, Yale University, New Haven, Connecticut, USA
Diabetes 59:2646-52. 2010..To determine whether the medial amygdalar nucleus (MAN) represents a novel brain glucose-sensing region involved in the detection of hypoglycemia and generation of a counterregulatory hormone response...
- Developmental gene x environment interactions affecting systems regulating energy homeostasis and obesityBarry E Levin
Neurology Service, VA Medical Center, E Orange, NJ 07018 1095, USA
Front Neuroendocrinol 31:270-83. 2010..These studies suggest that early identification of obesity-prone humans and of the factors that can prevent them from becoming obese could provide an effective strategy for preventing the world-wide epidemic of obesity...
- Characterization of beta-cell mass and insulin resistance in diet-induced obese and diet-resistant ratsSarah J Paulsen
Rheoscience A S, Rødovre, Denmark
Obesity (Silver Spring) 18:266-73. 2010..Collectively, the data support the use of HE-fed DIO rats as a model of human obesity and insulin resistance, and accentuate its relevance for studies examining the benefit of pharmaceutical compounds targeting this disease complex...
- Characteristics and mechanisms of hypothalamic neuronal fatty acid sensingChristelle Le Foll
Neurology Service, VA Medical Center, 385 Tremont Ave, East Orange, NJ 07018 1095, USA
Am J Physiol Regul Integr Comp Physiol 297:R655-64. 2009..This glucose-OA interaction provides a potential mechanism whereby such "metabolic sensing" neurons can respond to differences in the metabolic states associated with fasting and feeding...
- Effects of maternal genotype and diet on offspring glucose and fatty acid-sensing ventromedial hypothalamic nucleus neuronsChristelle Le Foll
Department of Neurology and Neurosciences, New Jersey Medical School, Newark, New Jersey, USA
Am J Physiol Regul Integr Comp Physiol 297:R1351-7. 2009..Such altered sensitivities may underlie the propensity of DIO offspring to become obese when fed high-fat, high-sucrose diets...