Reciprocal Modulation of Olfaction and Energy Balance via the Voltage-Gated Potassium Channel, Kv1.3

The voltage-gated potassium channel, Kv1.3, carries 60-80% outward current in the olfactory bulb (OB) primary output neuron, the mitral cell. Gene-targeted deletion of the Kv1.3, produces lean mice that have supernumerary and heterogeneous glomeruli and an increased ability to detect and discriminate odors. These skinny and "super-smeller" phenotypes exhibited by Kv1.3-null mice, suggest a role for Kv1.3 in both olfactory and metabolic sensitivity. To understand how Kv1.3 gene-targeted deletion affect mitral cell electrical sensitivity, the current evoked properties of mitral cells from Kv1.3-null and wildtype (WT) mice were evaluated by current-clamp slice electrophysiology. Gene-targeted deletion of Kv1.3 resulted in an increased action potential firing frequency, modified action potential kinetics, and a more depolarized resting membrane potential. These results suggest that decreased expression or conductance of Kv1.3 will increase the sensitivity of mitral cells to stimulation. There are several natural modulators of Kv1.3 activity including brain derived neurotrophic factor (BDNF), insulin, adenosine triphosphate (ATP) and reactive oxygen species (ROS) that are also important metabolism related factors. ATP and ROS are products of glucose metabolism. Heterologously expressed Kv1.3 channels were found to be sensitive to D- but not L-glucose via voltage-clamp electrophyology. Mitral cells have previously been shown to be sensitive to BDNF and insulin via modulation of Kv1.3 activity, glucose sensitivity has not been examined. To understand how changing glucose concentrations affect mitral cell electrical sensitivity, the current evoked properties of mitral cells from Kv1.3-null and wildtype (WT) mice were evaluated in the presence of 0, 5, 10 and 20 mM D-glucose by current-clamp slice electrophysiology. Like the hypothalamus, the OB contained two populations of glucose-sensitive mitral cells; glucose excited and glucose inhibited. Mitral cells from Kv1.3-null mice were insensitive to changing glucose concentrations. To explore the correlation between Kv1.3, metabolism, and olfaction, 11 week old mice were maintained on a moderately high-fat diet (MHF, 32% fat) for 26 weeks. Following treatment, the systems physiological parameters of body weight, respiration, locomotion, and ingestive behaviors were quantified in a custom-designed, computer-interfaced, metabolic chamber. Diet-induced obese (DIO) mice exhibited a 47% increase in body weight where as Kv1.3-null mice were resistant to DIO as a result of a significant increase in basal metabolic rate linked to the MHF challenge. Bilateral olfactory bulbectomy (OBX) in a Kv1.3-null background yielded mice that were no longer resistant to DIO resulting in weight gain. OBX actually prevented the MHF-induced increase in basal metabolic rate in these Kv1.3-null mice. Selective, olfactory bulb specific blockade of Kv1.3 resulted in a selective upregulation of basal or light phase metabolic rate in MHF and, to a lesser extent, control fat-diet (CF) treated WT mice. These results suggest that natural changes in the sensitivity of the OB by modulation of Kv1.3 via energetically important molecules such as insulin and glucose, could contribute to the body's natural metabolic response to fat intake. Kv1.3 is also involved in weight and metabolic modulation in a genetic model of obesity. Gene-targeted deletion of Kv1.3 in a mouse model of genetic obesity, the melanocorton receptor 4-null (MC4R-null) mouse, reduced body weight by decreasing fat deposition and subsequent fasting leptin levels, without changing overall growth, fasting blood glucose, or serum insulin. Light-phase mass-specific metabolic rate and locomotor activity were not affected by genetic deletion of Kv1.3 in MC4R-null mice but dark-phase locomotor activity and mass-specific metabolism were significantly increased resulting in increased total energy expenditure. These results suggest that not only is the olfactory system modulated by energy availability, the olfactory system can also modulate energy balance. One way for the system to accomplish this is to modulate the sensitivity of the olfactory system output, the mitral cells, via Kv1.3 regulation.