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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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Beth Israel Deaconess Medical Center
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Martin, Cecilia; Navarro, VĂ­ctor M; Simavli, Serap et al. (2014) Leptin-responsive GABAergic neurons regulate fertility through pathways that result in reduced kisspeptinergic tone. J Neurosci 34:6047-56
Berglund, Eric D; Liu, Tiemin; Kong, Xingxing et al. (2014) Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat Neurosci 17:911-3
Shah, Bhavik P; Vong, Linh; Olson, David P et al. (2014) MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc Natl Acad Sci U S A 111:13193-8
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
Garfield, Alastair S; Lowell, Bradford B (2013) Was it something I ate? Cell Metab 18:769-70
Krashes, Michael J; Shah, Bhavik P; Koda, Shuichi et al. (2013) Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab 18:588-95
Fujikawa, Teppei; Berglund, Eric D; Patel, Vishal R et al. (2013) Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab 18:431-44
Li, Chia; Pleil, Kristen E; Stamatakis, Alice M et al. (2012) Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the stria terminalis by kappa opioid receptor signaling. Biol Psychiatry 71:725-32
Liu, Tiemin; Kong, Dong; Shah, Bhavik P et al. (2012) Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73:511-22
Cohen, Jeremiah Y; Haesler, Sebastian; Vong, Linh et al. (2012) Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482:85-8

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