Glutamatergic Neurocircuitry Underlying MC4R Action Brain control of energy balance prevents obesity. An important component of this central regulation is the melanocortin system, which, working through melanocortin-4 receptors (MC4Rs), promotes weight loss. Indeed, absence of MC4Rs causes marked hyperphagia and massive obesity. Despite certainty regarding the importance of MC4Rs, there is a comparative lack of information regarding the underlying neurocircuitry. The goal of our studies is to understand the neural basis for MC4R-mediated regulation of energy balance. We have discovered that MC4Rs on both Sim1+ (likely the paraventricular nucleus - PVN) and Sim1- neurons (see below) control food intake. Of interest, MC4Rs on these two classes of neurons (Sim1+ and Sim1-) are functionally redundant, suggesting that they are interconnected. In a parallel set of studies, we have also discovered that the food intake- and body weight-regulating MC4Rs are located exclusively on glutamatergic (excitatory) neurons (marked by VGLUT2). Based upon these findings, and the work of others, we propose a novel, interconnected "glutamatergic network" to account for MC4R action. In this model, MC4Rs controlling food intake is on three groups of glutamatergic (excitatory) neurons. Two groups are Sim1-, are in the hindbrain, and constitute a linear, ascending, glutamatergic pathway that relays satiety signals from the gut to the forebrain (vagal afferents ->NTS ->lateral parabrachial nucleus (L-PBN)). The third group is Sim1+, is in the PVN, and sends descending, excitatory projections to the ascending pathway (at the NTS and L-PBN). AgRP and POMC neurons project to and engage MC4R-bearing glutamatergic neurons at each of these three sites. By placing MC4R-expressing neurons into an interconnecting pathway regulating satiety, this distributed model of melanocortin action accounts for the redundancy of MC4Rs on Sim1+ versus Sim1- neurons.
Three Aims will probe this model.
In Aim 1, we will test the underlying premises upon which the model is based (sufficiency versus necessity of MC4Rs on Sim1+ neurons, VGLUT2+ neurons, as well as on neurons in the PVN, NTS and L-PBN).
In Aim 2, we will a) identify the key Sim1+/VGLUT2+ neurons within the PVN, b) use optogenetics to test connectivity (PVN ->NTS and PVN ->L-PBN), and then c) use DREADD technology to remotely, acutely and reversibly modulate function in vivo.
In Aim 3, we will focus on the Sim1-/VGLUT2+ neurons in the NTS and L-PBN. In total, investigation of this distributed, interconnected, glutamatergic model of MC4R action should shed new light on neural circuits regulating food intake and energy balance.

Public Health Relevance

Complex neurocircuits in the brain, including the melanocortin pathway, work in concert to prevent obesity. In order to intelligently develop anti-obesity therapies, it is first necessary to decipher the "wiring-diagrams" that underpin these circuits. To accomplish this, our group is using the following state-of-the-art technologies: 1) neuron-specific gene manipulations to determine function, 2) optogenetics (light-activated neuron stimulation) to establish how the circuits are wired, and 3) DREADD technology to remotely, acutely and reversibly control circuit activity in vivo.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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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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