Leptin, by acting on leptin receptors (LEPRs) in the brain, exerts marked anti-obesity effects. Since the effects are large and specific, there is great interest in understanding their neural basis (the neurons and neurotransmitters that are involved). To identify the leptin-responsive neurons that initiate leptin's anti-obesity effects, we are genetically deleting LEPRs, in a neuron-specific fashion, and then assessing effects on energy balance. Our earlier studies established that POMC, AgRP and SF1 neurons are involved. However, it is also clear from these studies that a major part of the story is missing - other """"""""first-order"""""""", leptin-responding neurons must also be playing an important role. To identify these """"""""other"""""""" neurons, we are employing a novel approach - testing leptin-responsive, """"""""first-order"""""""" neurons based upon the fast-acting neurotransmitter that they release (i.e. glutamate (excitatory) or GABA (inhibitory)). Towards these ends, we have generated mice that express cre-recombinase in either glutamatergic (VGLUT2-ires-Cre mice) or GABAergic neurons (VGAT-ires-Cre mice). After this, we then created mice that lack LEPRs on glutamatergic or GABAergic neurons. Our preliminary studies indicate that leptin's anti-obesity effects are mediated predominantly by LEPRs on GABAergic neurons. This finding suggests a new logic for piecing together leptin-regulated neural circuits (i.e. a key role for GABAergic inhibitory neurons). Specifically, we propose that leptin action on """"""""local"""""""" GABAergic interneurons """"""""indirectly"""""""" controls the activity of principle body weight-regulating projection neurons (POMC and possibly AgRP neurons in the arcuate nucleus). A number of approaches are being used to probe this novel hypothesis. These include: 1) Genetic manipulation of LEPRs on GABAergic neurons (and subsets of GABAergic neurons) (in Aims One and Two), 2) Anatomic and electrophysiological analyses to determine the location, identity and function of the relevant leptin-responsive GABAergic neurons (in Aims Two and Three), and 3) Channelrhodopsin-assisted circuit mapping (CRACM) to test the functional connectivity between """"""""upstream"""""""" leptin-responsive GABAergic neurons and """"""""downstream"""""""" body weight-regulating POMC neurons (in Aim Three). Our hypothesized model is of interest because leptin-responsive GABAergic neurons could be important substrates for nutritional programming and/or metabolic plasticity.

Public Health Relevance

Neurocircuits in the brain control body fat stores. To develop anti-obesity therapies, we must first decipher the wiring-diagrams that underpin these circuits. We are using the following approaches to interrogate neural circuits engaged by the anti-obesity hormone, leptin: 1) neuron-specific gene manipulations, 2) optogenetics (light-activated neuronal stimulation) for probing circuit connectivity, and 3) electrical assessments of neuronal function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089044-04
Application #
8495327
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2010-08-05
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$324,150
Indirect Cost
$137,857
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Mandelblat-Cerf, Yael; Kim, Angela; Burgess, Christian R et al. (2017) Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons. Neuron 93:57-65
Livneh, Yoav; Ramesh, Rohan N; Burgess, Christian R et al. (2017) Homeostatic circuits selectively gate food cue responses in insular cortex. Nature 546:611-616
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
Cheng, Longzhen; Duan, Bo; Huang, Tianwen et al. (2017) Identification of spinal circuits involved in touch-evoked dynamic mechanical pain. Nat Neurosci 20:804-814
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
Resch, Jon M; Fenselau, Henning; Madara, Joseph C et al. (2017) Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling. Neuron 96:190-206.e7
Andermann, Mark L; Lowell, Bradford B (2017) Toward a Wiring Diagram Understanding of Appetite Control. Neuron 95:757-778
Garfield, Alastair S; Shah, Bhavik P; Burgess, Christian R et al. (2016) Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci 19:1628-1635
Nakajima, Ken-ichiro; Cui, Zhenzhong; Li, Chia et al. (2016) Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Nat Commun 7:10268
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

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