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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Biological Sciences
First Advisor
Marianna Sadagurski
Abstract
Evidence of the brain’s ability to regulate glucose and energy metabolism, and the role of the hypothalamus as the main regulator of whole-body homeostasis has been emerging, yet our limited understanding of the physiologic systems that regulate these processes impairs the ability to design novel therapeutics for various metabolic conditions. Neuroinflammation is increasingly recognized as one of the causal factors in the pathology of metabolic diseases. Glial cells (microglia and astrocytes) have recently garnered specific attention for their role in neuroinflammatory responses in metabolic disorders including obesity and metabolic imbalance. Microglia, produce various pro-inflammatory molecules that are critical for the development of peripheral metabolic imbalance and insulin resistance via hypothalamic inflammation. The central goal of this work was to investigate the hypothalamic regulation of metabolism and neuron-glia interactions in states of obesity or exposure to environmental toxins. This goal was achieved with genetically modified mice models and a novel murine model of air pollution, combining molecular, and physiological approaches designed to manipulate the inflammatory activation state of resident microglia. As part of our long-term goal to characterize the key subsets of hypothalamic neuroendocrine neurons that respond to an obesogenic environment, first, we identified neuroanatomically-restricted sets of hypothalamic growth hormone receptor (GHR) positive neurons in the arcuate nucleus (ARC) of the hypothalamus that are highly expressed in orexigenic agouti-related peptide (AgRP) neurons, while deleting GHR from AgRP neurons alters thermogenesis in the sex-specific manner. We next focused on the cellular and molecular interplay between hypothalamic neurons and microglia, in response to obesogenic environment and the induction of endoplasmic reticulum (ER) stress response. We discovered that hypothalamic microglial ER stress response driven by a high-fat diet is a critical mediator of peripheral metabolic imbalance, while loss of IRE1α, the most evolutionary conserved pathway of the unfolded protein response, protects male mice against diet-induced obesity. Finally, we reveal that exposure to environmental toxins, specifically benzene, promotes robust hypothalamic glial activation and elevation in the hypothalamic inflammatory IKKβ/NF-κB signaling pathway followed by the induction of ER stress response. Selective ablation of IKKβ in microglia alleviated benzene-induced hypothalamic inflammation, restored energy homeostasis, and protected against benzene-induced hyperglycemia. Thus, we demonstrate that the microglial NF-κB pathway plays a critical role in chemical-induced metabolic disturbances, revealing a vital pathophysiological mechanism linking exposure to airborne toxicants and the onset of metabolic diseases. Our findings emphasize the complex interplay between environmental/nutrient stressors and hypothalamic glia-neuronal interactions, demonstrating the potential mechanisms underlying central control of metabolic diseases.
Recommended Citation
Stilgenbauer, Lukas, "Hypothalamic Control Of Metabolism Under Stress Conditions" (2024). Wayne State University Dissertations. 4125.
https://digitalcommons.wayne.edu/oa_dissertations/4125