High-Fat Diet Induces Mitochondrial Dysfunction in Saphenous Nerve Axons—A Study by Confocal Microscopy In Vivo

Diabetic peripheral neuropathy (DPN) is a common, progressive and irreversible complication of diabetes (DM). Glucose regulation has no effect on the development and/or progression of the disease in type 2 DM and so, as the prevalence of DM increases, there is a growing unmet need for a mechanism-based therapy. We have examined the effect of high fat diet (HFD, 60% kcal fat) on axonal mitochondrial membrane potential and intra-axonal Ca 2+ concentration [Ca 2+ ] i in C56Bl/6 mice, in vivo , using confocal microscopy. The HFD resulted in obesity, hyperglycaemia and glucose intolerance. Mitochondria within saphenous nerve axons of mice fed a HFD for 16 or 36 weeks were significantly depolarised compared with those in mice fed a control diet. Furthermore, HFD mitochondria did not depolarise in response to high frequency electrical stimulation, in contrast to controls where depolarisation is associated with the increased energy demand of sustained impulse conduction. Confocal microscopy revealed that the number of mobile mitochondria was significantly greater in electrically active axons after 16 weeks of HFD, compared with controls, whereas after 36 weeks the number was significantly lower. Histologically, these changes were accompanied by significantly increased labelling for the mitochondrial biogenesis marker PGC1α in neuronal cell bodies at 16 weeks, but a reduction at 36 weeks, consistent with exhaustion of compensatory mechanisms activated early in the disease course. Interestingly, we found that [Ca 2+ ] i was decreased in mice fed a HFD. We conclude that a HFD impairs axonal mitochondrial function early in the course of type 2 MD. Impaired ATP production, especially during sustained impulse activity, may be a mechanism in the development of DPN. Disclosure M. Sajic: None. A. Kanhai: None. G. Dentoni: None. S. Varatharajah: None. L.M. Hinder: None. A. Rumora: None. E.L. Feldman: None. K. Smith: None.