Olfactory bulbectomy-induced impairment of lipid utilization leads to abnormal glucose metabolism in mice

Increased lipid utilization after food odor perception is a recently identified Pavlovian cephalic phase response in fasted mice that serves to prevent diet-induced glucose intolerance. However, the impact of olfactory dysfunction on metabolic functions remains unclear. Since olfactory bulbectomized (OBX) rodents have been used as a model of irreversible complete anosmia, we investigated whether glucose, lipid, and energy metabolism change over time in OBX mice fed a normal chow diet (NCD) or high-fat diet (HFD). OBX caused constant hyperactivity and triphasic temporal changes in lipid and glucose metabolism. In the early stage, OBX disrupted the olfactory regulation of lipid utilization and reduced fasting serum fatty acid levels without affecting glucose tolerance. In the middle stage (10-40 weeks after OBX on NCD; 5-10 weeks after OBX on HFD), OBX mice showed a mild reduction in body weight gain and improved glucose tolerance. In the later stage, glucose tolerance did not improve in NCD-fed OBX mice, while glucose tolerance was impaired and the expression of hepatic genes related to lipid metabolism was abnormal in HFD-fed OBX mice. In the absence of orexin, which regulates the brain-liver network, HFD-fed OBX mice showed an improvement in, but not the subsequent impairment of glucose tolerance. These results suggest that OBX rapidly impairs lipid metabolism, which gradually exacerbates glucose metabolism, whereas the associated hyperactivity contributes to improvements in glucose metabolism. Therefore, the olfactory bulb plays an essential role in the maintenance of lipid and glucose homeostasis.