THE EFFECTS OF NPY AND HIGH FAT, HIGH SUGAR DIET ON NTS NEURON SUBPOPULATIONS

Obesity and its associated metabolic disorders pose an increasingly common risk to human health. Obesity results from an excess of energy intake compared to energy expenditure. Communication between the gastrointestinal tract (GI) and the central nervous system (CNS) controls food intake via food-seeking appetitive and food intake-inhibiting or meal-terminating satiation signals. Many neurotransmitters, peptides, and hormones are involved in stimulating and inhibiting food intake. The orexigenic peptide neuropeptide Y (NPY) is released throughout the CNS to stimulate food intake and is important for preventing starvation in adult animals. Conversely, the CNS actions of the anorexigenic hormone leptin are necessary to limit food intake, as individuals with disrupted leptin signaling or loss-of-function of the leptin receptor (LepR) develop severe obesity. One brain region critical for the control of food intake is the nucleus of the solitary tract (NTS) in the brainstem. The NTS receives GI information from the vagus nerve that it integrates with signals from other brain regions involved in energy homeostasis, as well as potentially circulating factors including leptin. Excitation of NTS neurons results in the relaying of vagal afferent information throughout the CNS to control appetite, meal size, and feeding behavior. Though the effects of many food intake-stimulating and intake-inhibiting signals within the NTS have been examined, the mechanisms underlying many of these signal’s effects on NTS neuron subpopulations are yet to be investigated. Additionally, high fat, high sugar diets (HFHSDs) dysregulate the control of food intake by reducing the efficacy of satiety signals, including those transmitted by the vagus nerve during a meal. This results in increased meal size and weight gain that can lead to the development of obesity. However, HFHSD-induced dysregulation of vagal activation of NTS neurons is less well understood. For the following studies, I performed patch-clamp electrophysiology in transgenic mouse hindbrain slices to determine the effects of NPY, as well as a 3-week HFHSD, on two NTS neuron subpopulations vital for the control of meal size. In Chapter II, I established that NPY inhibits the vagal-evoked currents in NTS CA neurons via presynaptic Y2 receptors, resulting in reduced throughput of vagal-evoked action potentials. NPY and a Y2 receptor agonist also inhibits both basal and CCK-induced spontaneous glutamate release, corresponding with decreased basal action potential firing. In Chapter III, I show that a 3-week HFHSD reduces vagal activation of LepR-expressing NTS neurons in males, while potentially increasing their activation in females. I also report the effect of HFHSD on neuronal excitability and CCK-induced increases in spontaneous glutamate release. These mechanisms may contribute to the early detrimental effect of HFHSD consumption seen in male, but not female, mice. Collectively, this data expands upon our existing knowledge of the effects of orexigenic and anorexigenic signals, as well as the influence upon those factors by increasingly common HFHSDs, on the NTS circuitry.

Topic: Regulation of Appetite and Obesity
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences