Tuesday, May 7, 2024
5/7/2024
Obesity is a major health problem in the United States and a leading contributor to cardiovascular disease, diabetes mellitus and stroke. One region essential for the control of meal size is the nucleus of the solitary tract (NTS) in the brainstem. Vagal afferent fibers carrying different types of satiety information from the GI terminate in the NTS, and NTS neurons process this information before relaying it on to other brain regions to terminate a meal. Activation of NTS neurons therefore critically impacts meal length. However, NTS neurons are extremely heterogeneous in their expression of peptides and receptors. Activation of most NTS neuronal populations inhibits FI, including general activation of NTS neurons expressing catecholamines (NTS-CA). However, recently a subpopulation of NTS-CA neurons that express NPY and project to the arcuate nucleus were found to stimulate FI. Interestingly, intra NTS injections of NPY stimulates FI. Furthermore, our preliminary data suggest that both NPY and NE inhibit vagal activation of NTS neurons and that stimulating NTS NPY neurons inhibits neighboring NTS neurons. Taken together, these are intriguing results, but there are critical gaps in our knowledge about how these neurons impact the activity of other NTS neurons, how NTS NPY neurons are activated and if their function changes with metabolic state. Our central hypothesis for this proposal is that NTS NPY neurons release NPY and NE locally to inhibit anorexigenic NTS neurons and the level of release is determined by a balance of excitatory vagal drive and GABA inhibition, which is impacted by fasting and diet. We will test this hypothesis rigorously and comprehensively by pursuing the following specific aims: Aim 1. Determine the effects of locally released NPY and NE on NTS neuronal function. Aim 2. Elucidate what determines the activity of NTS NPY expressing neurons. Aim 3. Determine whether the activity of NTS NPY neurons and the effects of NPY and NE are altered during a fast and following a high fat high sugar (HFHS) diet. These studies are conceptually innovative because they focus on an under-investigated area: how orexigenic neurons integrate with other NTS neurons and the effect of metabolic state. They are rigorously and comprehensive as they use multiple complementary approaches. These results are expected to positively impact the field as they will elucidate underappreciated circuitry in a brain region well established for being critical for the control of food intake. This is anticipated to help direct and improve therapeutic strategies for the prevention and treatment of obesity.
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