Date of Award
8-8-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Communication between the nervous system and metabolic tissues directs whole body homeostasis. It is well understood that peripheral tissues respond to neural stimulation or inhibition to modulate energy usage and storage, hormone release, and stress pathways, but the neuroendocrine circuits that drive these outcomes remain ill-defined. Our lab identified sterile alpha and TIR motif containing 1 (SARM1) as the central executioner of axon degeneration in injury and disease models. We found that SARM1 is activated by an elevated NMN/NAD+ ratio and that nicotinamide analogs, including 3-AP and vacor, are converted to NMN-like intermediates that directly bind to SARM1, mimicking the endogenous stimulatory mechanism, to induce neurodegeneration. In addition to axon loss, these drugs have also been shown to trigger hyperglycemia and ketosis. Here, I show that 3-AP induces metabolic dysfunction in mice, including elevated blood glucose, ketone, free fatty acid, and glycerol levels, via the activation of SARM1. Systemic SARM1 activation by 3-AP also leads to a significant reduction in plasma insulin, with no change in glucagon. This drop in insulin does not stem from β cell death but instead from sympathetic signaling through α2A adrenergic receptors. Prior adrenalectomy protects against SARM1-induced metabolic dysfunction, pointing to a stimulation of the sympathoadrenal medullary (SAM) pathway that is canonically employed during stress to trigger fuel catabolism and block glucose uptake. The work presented here identifies a novel role for SARM1 as a driver of sympathetic signaling and hyperglycemia upon 3-AP treatment, laying the foundation for future work characterizing the neurocircuit employed here and the potential contexts in which this SARM1-dependent pathway is utilized, including during stress or hypoglycemia.
Language
English (en)
Chair and Committee
Aaron DiAntonio
Committee Members
Brian Finck; Clay Semenkovich; Shin-ichiro Imai; Thomas Baranski
Recommended Citation
Spatz, Lillian, "Systemic Activation of the Axon Degeneration Executioner SARM1 Triggers Acute Hyperglycemia" (2024). Arts & Sciences Electronic Theses and Dissertations. 3323.
https://openscholarship.wustl.edu/art_sci_etds/3323