Researcher Profile

Vanessa H. Routh, PhD

Professor of Pharmacology and Physiology and Neurosciences
New Jersey Medical School
Rutgers, The State University of New Jersey

Medical Science Building
185 South Orange Avenue
Newark, NJ 07103

Phone: (973) 972-1489
Email: routhvh@njms.rutgers.edu

Research Program Alignment

Membership Type: Full


Research Interests

  • Central Mechanisms in the Regulation of Energy Balance
  • Disease Applications: Type 1 and 2 Diabetes Mellitus, Insulin-Induced Hypoglycemia, Hypoglycemia-Associated-Autonomic-Failure, Obesity, Disease-related Anorexia and/or Cachexia
  • Our overall hypothesis is that the maintenance of energy balance is a critical function of the brain. We are particularly interested in specialized "glucose sensing" neurons which sense and respond to nutrient (i.e., glucose, lactate, fatty acids) and hormonal (i.e., insulin, leptin) changes in the extracellular milieu of the brain. While glucose sensing neurons exist in many regions of the brain, we primarily focus on understanding the mechanisms underlying the regulation of the glucose sensitivity of hypothalamic glucose sensing neurons. There are two types of hypothalamic glucose sensing neurons. Glucose-excited (GE) neurons decrease while glucose-inhibited (GI) neurons increase their action potential frequency as extracellular glucose decreases. Like pancreatic beta cells, decreased glucose opens an ATP-sensitive potassium channel and inhibits GE neurons. In contrast, decreased glucose activates an AMP-activated protein kinase (AMPK)-nitric oxide (NO) signaling pathway in GI neurons which closes a chloride channel leading to depolarization and activation.
  • We believe that GE and GI neurons evolved to sense energy and/or glucose deficit such as that seen during a severe fast. Under fasting conditions they are part of a neuronal circuitry which compensates for energy deficit by activating energy conserving processes and inhibiting energy consuming processes. In so doing, GE and GI neurons ensure that the brain has an adequate glucose supply for normal function. This system clearly fails during disease (e.g., cancer) related anorexia cachexia. We also believe that GE and GI neurons play an important role in restoring blood glucose levels following the modern problem of iatrogenic insulin-induced hypoglycemia in patients with Type 1 and advanced Type 2 Diabetes Mellitus. Moreover, an inability of GE and GI neurons to sense decreased glucose is associated with an impaired ability of the brain to restore euglycemia during hypoglycemia associated autonomic failure, a major side effect of insulin therapy during diabetes.
  • At the present time, there are 3 major areas of research in our laboratory which investigates dysfunctional glucose sensing by GE and GI neurons during the following disease-related abnormalities in whole body energy and/or glucose homeostasis:
  • 1. Hypoglycemia-associated autonomic failure (HAAF). Insulin therapy in patients with Type 1 or advanced Type 2 Diabetes Mellitus is required to prevent complications of hyperglycemia. However, intensive insulin therapy has a severe side effect: hypoglycemia. Unfortunately, even one episode of hypoglycemia can impair the ability of the brain to sense hypoglycemia and initiate corrective mechanisms to restore blood glucose levels, a condition known as HAAF. We have found that the ability of glucose sensing neurons to sense glucose deficit is also impaired in an animal model of HAAF. This may be due, in part, to nitric oxide resistance in GI neurons as a result of increased oxidative stress during hypoglycemia.
  • 2. Type 2 Diabetes Mellitus (T2DM) and Obesity . The satiety hormones, insulin and leptin, prevent GE and GI neurons, respectively, from responding to small glucose decreases. We believe that this prevents the activation of strong compensatory metabolic circuits in response to decreases in glucose seen between meals. However, glucose sensing neurons become sensitized to decreased glucose under conditions where insulin and leptin levels are low (e.g., fasting) or as a result of insulin resistance during T2DM. We hypothesize that increased sensitivity of glucose sensing to small daily decreases in glucose may lead to signals of energy and/or glucose deficit in the presence of energy sufficiency or even excess. Such changes in glucose sensitivity may lead to activation of mechanisms which favor energy storage over expenditure and exacerbate obesity and diabetes.
  • 3. Disease-related anorexia cachexia . This new project in our laboratory tests the hypothesis that the sensitivity of glucose sensing neurons to glucose deficit becomes impaired in diseases associated with anorexia and cachexia (e.g., inflammation, cancer). Such a change in glucose sensitivity would lead to the opposite effect as that described above. Under these conditions, glucose decreases would not be detected and compensatory mechanisms would not be initiated even under conditions of severe energy deficit. Our data using models of sepsis and cancer anorexia are consistent with this hypothesis.
  • In order to address these issues we use a variety of in vivo and in vitro techniques including electrophysiology (patch clamp) in brain slices and isolated neurons, microscopy/imaging in primary hypothalamic cultures, hypothalamic peptide release, stereotaxic surgery and hyperinsulinemic/hypoglycemic clamps in vivo , as well as standard immunohistochemical, biochemical and molecular techniques.

The content for this Research Profile is maintained by Paul Novembre (novembre@cinj.rutgers.edu)