Have you ever noticed when you are hungry and looking for something to eat, you can smell the freshly salted fries of McDonalds before seeing the golden arches? That is because our sense of smell, olfaction, is intimately linked with metabolic state and feeding behavior. In fact, many of the circulating hormones and gut peptides that regulate feeding behaviors have receptors located in the olfactory bulb (OB), and thus, have been reported to influence olfactory functioning; increasing sensitivity while hungry and decreasing odor perception once satiated. If metabolic state becomes disrupted, as observed in metabolic disorders such as obesity and Type 2 Diabetes, this can negatively impact one’s sense of smell, which is why many obese and/or diabetic patients also display symptoms of anosmia, or loss of smell. My laboratory has pinpointed the OB as an internal metabolic sensor, in particular, the mitral cells (MCs) within the OB, which are the major output neurons of the OB and are responsible for sending signals to higher-order processing regions in the brain. Gut peptides and important metabolic factors such as insulin and glucose can increase MC firing frequency via modulation of the voltage-gated potassium channel, Kv1.3. Kv1.3 channels are widely distributed across the body, but are highly expressed in the OB and predominantly located on MCs; Kv1.3 channel carries 60 – 80% of the outward current of these cells. The central theme of my dissertation involves understanding how excess energy substrates can perturb the operation of the brain to effect behavior of the organism. My research involves specifically targeting Kv1.3, that is modulated by circulating neuropeptides and hormones. Our laboratory has demonstrated gut peptides and important metabolic factors such as insulin, glucose, and glucagon-like peptide -1 (GLP-1) can increase MC firing frequency via modulation of Kv1.3, and ultimately modify olfactory and metabolic behaviors. This dissertation examines two aspects in which energy substrates modulate Kv1.3 activity, behaviorally and physiologically. Results from these experiments revealed that 1. Long-term intranasal delivery of insulin does not affect olfactory or metabolic behaviors, but changes meal bout and dampens Kv1.3 phosphorylation. 2. Intranasal delivery of the specific Kv1.3 inhibitor, stichodactyla (ShK) 186 toxin, partially improves metabolism in obese animals. 3. GLP-1 modulates Kv1.3 activity via serine phosphorylation. This work will further expand upon how feeding-related hormones can shape olfactory ability and bring forth new insight into using sensory systems to control food intake and overconsumption, a leading cause of obesity in America.
