Glucose-Sensing by Neurons: its Importance and the Role of UCP2 Glucose-sensing by the brain is a well documented phenomenon with potentially important implications for the pathogenesis of type 2 diabetes. Prior electrophysiological studies have determined that subpopulations of neurons are regulated by glucose. As glucose rises, """"""""glucose-excited"""""""" neurons depolarize and increase their firing rate. Examples of glucose-excited neurons include POMC neurons in the arcuate nucleus, MCH neurons in the lateral hypothalamus and a subgroup of neurons in the ventromedial hypothalamus (VMH). The molecular apparatus responsible for excitation by glucose is thought to have similarities to that found in pancreatic (3-cells. Specifically, neuronal oxidation of glucose and/or lactate (thelatter generated by glucose metabolism in glial cells), increases the ATP/ADP ratio. This then closes neuronal KATP channels, depolarizing the neuron which then increases its firing rate. While the phenomenon of """"""""P-cell-like"""""""" glucose- sensing in the brain is robust, its physiologic relevance and its contribution to disease states such as type 2 diabetes, is unknown. The overall goal of these studies is to assess the role of """"""""p-cell-like"""""""" glucose-sensing by neurons in normal physiology and in the development of type 2 diabetes. This will be accomplished through the use of genetically engineered mice. First, we will disrupt """"""""P-cell-like"""""""" glucose-sensing in a neuron-specific fashion, through transgenic expression of a mutant KATP channel, and then determine if this adversely affects insulin / glucose homeostasis (Aim 1). Second, we will determine if uncoupling protein-2 (UCP2) negatively regulates """"""""P-cell-like"""""""" glucose-sensing in neurons and whether this could be a cause of defective glucose-sensing in type 2 diabetes (Aim 2). Third, we will determine if absence of UCP2 in neurons, which we predict will prevent loss of glucose-sensing, improves obesity-induced impairments in insulin / glucose homeostasis (Aim 3). Studies proposed in this application could provide novel insight into the role of the brain in the pathogenesis of type 2 diabetes. Such insight could result in novel treatments for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK053477-14
Application #
8030416
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
1998-01-15
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
14
Fiscal Year
2011
Total Cost
$334,733
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Fenselau, Henning; Campbell, John N; Verstegen, Anne M J et al. (2017) A rapidly acting glutamatergic ARC?PVH satiety circuit postsynaptically regulated by ?-MSH. Nat Neurosci 20:42-51
Campbell, John N; Macosko, Evan Z; Fenselau, Henning et al. (2017) A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20:484-496
Garfield, Alastair S; Shah, Bhavik P; Burgess, Christian R et al. (2016) Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci 19:1628-1635
Crowley, Nicole A; Bloodgood, Daniel W; Hardaway, J Andrew et al. (2016) Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit. Cell Rep 14:2774-83
Krashes, Michael J; Lowell, Bradford B; Garfield, Alastair S (2016) Melanocortin-4 receptor-regulated energy homeostasis. Nat Neurosci 19:206-19
Kong, Dong; Dagon, Yossi; Campbell, John N et al. (2016) A Postsynaptic AMPK?p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons. Neuron 91:25-33
Vetrivelan, Ramalingam; Kong, Dong; Ferrari, Loris L et al. (2016) Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 336:102-113
Al-Hasani, Ream; McCall, Jordan G; Shin, Gunchul et al. (2015) Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward. Neuron 87:1063-77
Garfield, Alastair S; Li, Chia; Madara, Joseph C et al. (2015) A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 18:863-71
Krashes, Michael J; Shah, Bhavik P; Madara, Joseph C et al. (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507:238-42

Showing the most recent 10 out of 22 publications