Date of Award

Spring 5-10-2019

Level of Access

Open-Access Thesis

Language

English

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Kristy Townsend

Second Committee Member

Alan Rosenwasser

Third Committee Member

Juergen Naggert

Additional Committee Members

Leonard Kass

Roger Sher

Abstract

Although the brain is the master regulator of all bodily functions, peripheral nerves provide a means by which the brain communicates to all tissues, regulates organ function, and maintains systemic homeostasis. Metabolic homeostasis relies on the maintenance of energy balance which is governed in large part by the brain and adipose tissue. Disruption of communication between these two organs can lead to a metabolic state of energy excess or insufficiency, i.e. energy imbalance. Energy balance is maintained when energy intake, governed by appetite, food intake and nutrient absorption, equates energy expenditure, which is influenced by physical activity, basal metabolic rate, and thermogenesis. Over the last few decades, surgical and chemical denervation studies have demonstrated how maintenance of brain-­adipose communication through both sympathetic efferent and sensory afferent nerves helps regulate adipocyte size, cell number, lipolysis, and ‘browning’ of white adipose tissue (the process by which energy iv storing adipose tissue becomes thermogenically active and expends energy). However, the factors that regulate peripheral nerve health and remodeling, defined to include neuropathy (nerve death) and plasticity (neurite outgrowth), within the adipose organ have not been well explored. Peripheral neuropathy is a condition of nerve die-­back that begins in the skin and travels inwards. Here we have shown that underlying subcutaneous adipose tissues also display peripheral neuropathy with conditions that range from obesity and diabetes to aging and certain diets. Under all aforementioned conditions the tissue also exhibited a loss of locally produced neurotrophic factors, which we have now implicated in the mechanism of adipose neuropathy. Exercise is able to at least partially reverse adipose neuropathy, and is associated with an increase in local neurotrophic factor expression. Furthermore, AAV-­mediated gene delivery of this neurotrophic factor was shown to increase innervation in subcutaneous adipose tissue in a murine model of diabetic peripheral neuropathy. Interestingly, exercise and cold stimulation are both able to increase gene and protein expression of pan-­neuronal and synaptic markers in adipose tissue, suggesting increased innervation of the tissue. We have also demonstrated that in adipose tissue, a neurotrophic factor is produced by immune cells in the stromovascular fraction, under stimulation from noradrenergic signaling. Deletion of this neurotrophic factor from myeloid lineage immune cells leads to a striking and specific ‘genetic denervation’ of white adipose tissue only, sparing the spinal nerves, neuromuscular junction, brain, and brown adipose tissue. Therefore, we believe we have uncovered a novel mechanism for how adipose tissue metabolic health is regulated through remodeling of the tissue’s peripheral nerve network.

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