Consumption of a Fatty Diet Promotes Obesity-Independent Olfactory Sensory Neuronal Loss

The metabolic state of an organism and their sense of olfaction are closely interrelated. There is significant evidence that olfactory signals can modulate multiple metabolic parameters and, in turn, that metabolically relevant signals can modulate the function of the olfactory system and olfactory behavior. Diet and exercise are two powerful metabolic forces. Poor diet and low levels of physical activity are associated with increased disease and cancer rates, higher overall mortality, pro-inflammatory immune state, disrupted neurogenesis and reduced cognitive ability. Conversely, regular participation in voluntary exercise is associated with decreased disease and cancer incidence, lower overall morality, lower inflammation, increased neurogenesis and improved cognition. The dangers of poor diet and the benefits of exercise are somewhat characterized in the periphery and in several select brain areas. Much less is known about how diet and exercise impact the olfactory system. Previous work in a rodent model demonstrated that long-term consumption of a high-fat diet resulted in, as expected, a significant increase of bodyweight and bodyfat as well as, and perhaps more surprisingly, a significant reduction in the number of olfactory sensory neurons. In these findings it is difficult to determine what caused the neuronal loss: the unhealthy diet or the overconsumption and concomitant weight gain and body composition changes. Additionally, whether the neuroprotective effects of voluntary exercise extend to the olfactory system is virtually unexplored. To address these questions, I fed mice the same obesogenic diet that has been shown to result in neuronal loss, but I used a system of daily pair-feeding to prevent overconsumption and weight gain in order to disentangle the effects of the diet per se from its metabolic consequences. In a separate experiment, I provided mice that were maintained on either a normal rodent chow or the obesogenic diet with access to a running wheel to assess the effects of long-term voluntary exercise on the olfactory system independently and in combination with the demonstrated effects of the unhealthy diet. Finally, I compared the voluntary exercise behavior of a transgenic mouse line with unique metabolic and olfactory phenotypes (genetic knockouts for a voltage gated potassium channel) to wildtype mice when maintained on two different diets. In the pair-feeding experiments, mice that were pair-fed with the obesogenic did not gain weight or adiposity, but they still displayed a significant reduction of olfactory sensory neurons equal to that of the obese mice that were provided unlimited access to the diet. Interestingly, both pair-fed and ad libitum-fed mice maintained on the high-fat diet displayed equal levels of the inflammatory cytokine tumor necrosis factor and comparable levels of impaired glucose metabolism despite vastly different bodyweights and adiposity. In the exercise experiments, providing mice with a running wheel partially combated the metabolic detriments associated with the fatty diet. Mice maintained on the high-fat diet and given a running wheel weighed less, had lower body fat, and slightly improved glucose metabolism compared to mice on the same diet without access to a wheel. However, these partial protections did not extend to the olfactory system as mice fed the fatty diet in combination with running wheel access still displayed a significant loss of olfactory sensory neurons. In fact, if anything long-term exercise may have a negative effect on the olfactory system as mice maintained on the normal chow with access to running wheels also displayed a slight, but not statistically significant reduction in olfactory sensory neurons, though no behavioral deficits were noted in any of the groups. Additionally, the potassium channel knockout mice and wildtype mice displayed similar levels of wheel running but exhibited altered running patterns. These data further display the intricate connection between olfaction and metabolic state. Strong metabolic drivers like diet modification and exercise can impact the neurons in the olfactory system. My data suggest an inflammatory link between consumption of a fatty diet and neuronal loss in the olfactory system that occurs independently of obesity and is not prevented by wheel running, though no causative link is demonstrated by these experiments. Future studies using diets of varying but closely matched compositions or a broader evaluation of inflammatory pathways are warranted to better understand the mechanisms underlying the bidirectional influences between olfaction and metabolism.