BADERC-Bradford B. Lowell

Bradford B. Lowell, M.D., Ph.D.

Genetic Dissection of Neurocircuits Controlling Energy Balance and Glucose Homeostasis

The Lowell Lab is an Integrative Molecular Physiology group, which utilizes genetic engineering techniques in mice to study central pathways controlling behavior and energy metabolism.

Our research group uses transgenic and gene knockout approaches to manipulate neuronal function in discrete populations of neurons. The ultimate goal of our studies is to link the function of a protein, within defined sets of neurons, with specific behaviors and physiologic processes. Genes being manipulated, in a neuron-specific fashion, include the leptin receptor, the melanocortin-4 receptor (MC4R), the ATP-regulated K channel (KATP channel, Kir6.2 subunit), uncoupling protein-2 (controls mitochondrial ATP production), the vesicular glutamate transporter-2 (VGLUT2 – packages glutamate into synaptic vesicles) the vesicular GABA transporter (VGAT – packages GABA into synaptic vesicles), and glutamate NMDA receptors. Specific questions being addressed include the following:

1) Leptin: Which leptin-responsive, “first order” neurons mediate the anti-obesity actions of leptin? What is the role of leptin action on POMC neurons, AgRP neurons and SF1 neurons? What is the role of leptin action on GABAergic versus glutamatergic neurons?

2) MC4Rs: Which neurons mediate the anti-obesity actions of MC4Rs? Through which neurons in the paraventricular nucleus do MC4Rs regulate food intake (oxytocin versus CRH versus AVP neurons)? Through which neurons do MC4Rs regulate energy expenditure (symapethic preganglionic neurons in the spinal cord versus raphe pallidus neurons in the brain stem)?

3) SF1 Neurons: How do SF1 neurons in the VMH regulate body weight? What effectors do they release to communicate with downstream neurons (role of glutamate versus PACAP)? How are the dendrites of SF1 neurons, and excitatory inputs passing through SF1 neurons controlled by glutamate NMDA receptors? Do NMDA receptors regulate synaptic plasticity in neural circuits controlling energy homeostasis? Does leptin-mediated regulation of NMDA receptor activity affect neuronal plasticity?

4) GABA and Glutamate: What are the roles of the inhibitory neurotransmitter, GABA, and the excitatory neurotransmitter, glutamate, in neurocircuits controlling energy balance and glucose homeostasis?

5) Glucose Sensing in the brain: What is the role of glucose sensing in POMC neurons, MCH neurons and VMH neurons in controlling whole body glucose homeostasis? Does dysregulation of these processes contribute to pathogenesis of type 2 diabetes.

6) UCP2 and Dopamine: Does mitochondrial function impact on the activity of dopamine neurons? Does this affect neural pathways controlling behavior, reward and addiction?

7) GPR101: What is the role of the orphan G-protein coupled receptor, GPR101, in controlling food intake?






			Bradford B. Lowell, M.D., Ph.D. Genetic Dissection of Neurocircuits Controlling Energy Balance and Glucose Homeostasis The Lowell Lab is an Integrative Molecular Physiology group, which utilizes genetic engineering techniques in mice to study central pathways controlling behavior and energy metabolism. Our research group uses transgenic and gene knockout approaches to manipulate neuronal function in discrete populations of neurons. The ultimate goal of our studies is to link the function of a protein, within defined sets of neurons, with specific behaviors and physiologic processes. Genes being manipulated, in a neuron-specific fashion, include the leptin receptor, the melanocortin-4 receptor (MC4R), the ATP-regulated K channel (KATP channel, Kir6.2 subunit), uncoupling protein-2 (controls mitochondrial ATP production), the vesicular glutamate transporter-2 (VGLUT2 – packages glutamate into synaptic vesicles) the vesicular GABA transporter (VGAT – packages GABA into synaptic vesicles), and glutamate NMDA receptors. Specific questions being addressed include the following: 1) Leptin: Which leptin-responsive, “first order” neurons mediate the anti-obesity actions of leptin? What is the role of leptin action on POMC neurons, AgRP neurons and SF1 neurons? What is the role of leptin action on GABAergic versus glutamatergic neurons? 2) MC4Rs: Which neurons mediate the anti-obesity actions of MC4Rs? Through which neurons in the paraventricular nucleus do MC4Rs regulate food intake (oxytocin versus CRH versus AVP neurons)? Through which neurons do MC4Rs regulate energy expenditure (symapethic preganglionic neurons in the spinal cord versus raphe pallidus neurons in the brain stem)? 3) SF1 Neurons: How do SF1 neurons in the VMH regulate body weight? What effectors do they release to communicate with downstream neurons (role of glutamate versus PACAP)? How are the dendrites of SF1 neurons, and excitatory inputs passing through SF1 neurons controlled by glutamate NMDA receptors? Do NMDA receptors regulate synaptic plasticity in neural circuits controlling energy homeostasis? Does leptin-mediated regulation of NMDA receptor activity affect neuronal plasticity? 4) GABA and Glutamate: What are the roles of the inhibitory neurotransmitter, GABA, and the excitatory neurotransmitter, glutamate, in neurocircuits controlling energy balance and glucose homeostasis? 5) Glucose Sensing in the brain: What is the role of glucose sensing in POMC neurons, MCH neurons and VMH neurons in controlling whole body glucose homeostasis? Does dysregulation of these processes contribute to pathogenesis of type 2 diabetes. 6) UCP2 and Dopamine: Does mitochondrial function impact on the activity of dopamine neurons? Does this affect neural pathways controlling behavior, reward and addiction? 7) GPR101: What is the role of the orphan G-protein coupled receptor, GPR101, in controlling food intake? References: Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr, Elmquist JK, Lowell BB. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42: 983-91, 2004. Equal Senior Authors. Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, Ferreira M, Tang V, McGovern RA, Kenny CD, Christiansen LM, Edelsttein E, Choi B, Boss O, Aschkenasi C, Zhang CY, Mountjoy M, Kishi T, Elmquist, Lowell BB.** Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123: 493-505, 2005. * Equal Senior authors. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V, Kenny CD, Christiansen LM, White RD, Edelstein EA, Coppari R, Balthasar N, Cowley MA, Chua Jr. SC, Elmquist JK, *Lowell BB.** Leptin directly activates SF1 neurons in the ventromedial hypothalamus and this action by leptin is required for normal body weight homeostasis. Neuron 49: 191-203, 2006. * Equal Senior authors. Zhang CY, Parton LE, Ye CP, Krauss S, Shen R, Porco Jr JA, Lowell BB. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced b-cell dysfunction in isolated pancreatic islets. Cell Metabolism 3: 417-427, 2006. Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B, Kramer MD, Yu J, Yang Z, Christiansen LM, Lee CE, Choi CS, Zigman JM, Shulman GI, Sherwin RS, Elmquist JK, Lowell BB. Glutamate release by ventromedial hypothalamic (VMH) neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metabolism 5: 383-93, 2007 (PMC1934926). Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, Xu C, Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley MA, Lowell BB. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449: 228-32, 2007 (PMID: 17728716). van de Wall E, Leshan R, Xu AW, Balthasar N, Coppari R, Liu SM, Jo YH, MacKenzie RG, Allison DB, Dun NJ, Elmquist J, Lowell BB, Barsh GS, de Luca C, Myers MG Jr, Schwartz GJ, Chua SC Jr. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149: 1773-85, 2008 (PMC2276717). Tong Q, Ye C, Jones JE, Elmquist JK, Lowell BB. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11: 998-1000, 2008 (PMC2662585).